6-azauracil derivatives as IL-5 inhibitors

ABSTRACT

The present invention is concerned with the use of compounds of formula                    
     the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein p represents 0, 1, 2 or 3; q represents 0, 1, 2, 3 or 4; R 1  represents hydrogen, C 1-6 alkyl, mono- or di(C 1-6 alkyl)aminoC 1-6 alkyloxy, mercapto, C 1-6 alkylthio, C 3-7 cycloalkyl, aryl or C 1-6 alkyl substituted with mono- or di(C 1-6 alkyl)-amino, C 1-6 alkyloxy, aryl or Het; R 2  represents cyano or a radical of formula —C(═X)—Y—R 5 ; wherein X represents O or S; Y represents O, S, NR 6  or a direct bond; R 5  represents hydrogen; C 3-7 cycloalkyl; aryl or optionally substituted C 1-6 alkyl; and where Y is a direct bond, R 5  may also be halo or Het; R 3  and R 4  each independently represents halo, haloC 1-6 alkyl, C 1-6 alkyl, hydroxy, C 1-6 alkyloxy, C 1-6 alkylcarbonyloxy, mercapto, C 1-6 alkylthio, C 1-6 alkylsulfonyl, C 1-6 alkylsulfinyl, haloC 1-6 alkylsulfonyl, aryl, cyano, nitro, amino, mono- and di(C 1-6 alkyl)amino or (C 1-6 alkylcarbonyl)amino; aryl represents phenyl or substituted phenyl; and Het represents an optionally substituted heterocycle; in the manufacture of a medicament useful for treating eosinophil-dependent inflammatory diseases. The invention also relates to novel compounds, their preparation and compositions comprising them.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Serial No. 09/462,323filed on Jan. 5, 2000, now abandoned, which is the National Stageapplication under 35 U.S.C. 371 of PCT/EP98/04192 filed Jul. 2, 1998,which claims priority from EP 97.202.117.4, filed Jul. 10, 1997.

The present invention concerns the use of IL-5 inhibiting 6-azauracilderivatives in the manufacture of a medicament useful for treatingeosinophil-dependent inflammatory diseases. It further relates tocertain novel 6-azauracil derivatives, to processes for theirpreparation and compositions comprising them.

Eosinophil influx, leading to subsequent tissue damage, is an importantpathogenic event in bronchial asthma and allergic diseases. The cytokineinterleukin-5 (IL-5), produced mainly by T lymphocytes as aglycoprotein, induces the differentiation of eosinophils in bone marrowand, primes eosinophils for activation in peripheral blood and sustainstheir survival in tissues. As such, IL-5 plays a critical role in theprocess of eosinophilic inflammation. Hence, the possibility thatinhibitors of IL-5 production would reduce the production, activationand/or survival of eosinophils provides a therapeutic approach to thetreatment of bronchial asthma and allergic diseases such as, atopicdermatitis, allergic rhinitis, allergic conjunctivitis, and also othereosinophil-dependent inflammatory diseases.

Steroids, which strongly inhibit IL-5 production in vitro, have longbeen used as the only drugs with remarkable efficacy for bronchialasthma and atopic dermatitis, but they cause various serious adversereactions such as diabetes, hypertension and cataracts. Therefore, itwould be desirable to find non-steroidal compounds having the ability toinhibit IL-5 production in human T-cells and which have little or noadverse reactions.

U.S. Pat. No. 4,631,278 disclosesα-aryl-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-benzeneacetonitrilesand U.S. Pat. No. 4,767,760 discloses 2-(substitutedphenyl)-1,2,4-triazine-3,5(2H,4H)-diones, all having anti-protozoalactivity, in particular, anti-coccidial activity. Unexpectedly, the6-azauracil derivatives of the present invention, including saidart-known 1,2,4-triazinedione derivatives, prove to be potent inhibitorsof the production of IL-5.

The present invention is concerned with the use of compounds of formula

the N-oxides, the pharmaceutically acceptable addition salts and thestereochemically isomeric forms thereof, wherein:

p represents an integer being 0, 1, 2, 3 or 4;

q represents an integer being 0, 1, 2, 3, 4 or 5;

R¹ represents hydrogen, C₁₋₆alkyl, mono- ordi(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, mercapto, C₁₋₆alkylthio, C₃₋₇cycloalkyl,aryl or C₁₋₆alkyl substituted with mono- or di(C₁₋₆alkyl)amino,C₁₋₆alkyloxy, aryl or Het;

R² represents cyano or a radical of formula —C(═X)—Y—R⁵; wherein

X represents O or S;

Y represents O, S, NR⁶ or a direct bond;

R⁵ represents hydrogen; C₁₋₆alkyl; C₃₋₇cycloalkyl; aryl or C₁₋₆alkylsubstituted with aryl, hydroxy or Het; and where Y is a direct bond, R⁵may also be halo or Het;

R⁶ represents hydrogen, C₁₋₆alkyl, C₁₋₆alkyloxy or arylC₁₋₆alkyl;

each R³ independently represents halo, haloC₁₋₆alkyl, C₁₋₆alkyl,hydroxy, C₁₋₆alkyloxy, C₁₋₆alkylcarbonyloxy, mercapto, C₁₋₆alkylthio,C₁₋₆alkylsulfonyl, C₁₋₆alkylsulfinyl, haloC₁₋₆alkylsulfonyl, aryl,cyano, nitro, amino, mono- and di(C₁₋₆alkyl)amino or(C₁₋₆alkylcarbonyl)amino;

each R⁴ independently represents halo, haloC₁₋₆alkyl, C₁₋₆alkyl,hydroxy, C₁₋₆alkyloxy, C₁₋₆alkylcarbonyloxy, mercapto, C₁₋₆alkylthio,C₁₋₆alkylsulfonyl, C₁₋₆alkylsulfinyl, haloC₁₋₆alkylsulfonyl, aryl,cyano, nitro, amino, mono- and di(C₁₋₆alkyl)amino or(C₁₋₆alkylcarbonyl)amino;

aryl represents phenyl or phenyl substituted with one, two or threesubstituents selected from the group comprising halo, C₁₋₆alkyl,C₁₋₆alkyloxy, haloC₁₋₆alkyl, hydroxy, mercapto, C₁₋₆alkylthio,C₁₋₆alkylsulfonyl, C₁₋₆alkylsulfonyloxy, C₁₋₆alkylsulfinyl,haloC₁₋₆alkylsulfonyl, nitro, cyano, amino, mono- and di(C₁₋₆alkyl)aminoand C₁₋₆alkylcarbonylamino; and

Het represents a heterocycle selected from pyrrolyl, pyrrolinyl,pyrrolidinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl,triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl,dioxolanyl, oxazolyl, oxazolinyl, isoxazolyl, thiazolyl, thiazolinyl,isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl,pyrazinyl, pyranyl, pyridazinyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, dioxanyl, dithianyl, trithianyl, triazinyl,benzothienyl, isobenzothienyl, benzofuranyl, isobenzofuranyl,benzthiazolyl, benzoxazolyl, indolyl, isoindolyl, indolinyl, purinyl,benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phtalazinyl,quinazolinyl, quinoxalinyl and thiazolopyridinyl; said heterocycles eachindependently may be substituted with one, two or three substituentsselected from hydroxy, mercapto, C₁₋₄alkyl, C₁₋₄alkyloxy, cyano, amino,nitro, mono- or di(C₁₋₄alkyl)amino, mono- or di(C₁₋₄alkyl)aminocarbonyl,mono- or di(aryl)amino, halo, haloC₁₋₄alkyl, C₁₋₄alkyloxycarbonyl, aryl,furanyl, thienyl, pyridinyl, piperidinyl, C₁₋₄alkylcarbonylpiperidinyland C₁₋₄alkyl substituted with hydroxy, C₁₋₄alkyloxy, aryl, piperidinyl,amino, mono- or di(C₁₋₄alkyl)amino or C₃₋₇cycloalkyl;

in the manufacture of a medicament useful for treatingeosinophil-dependent inflammatory diseases.

The compounds of formula (I) are deemed novel, provided that theα-aryl-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetonitrilespublished in U.S. Pat. No. 4,631,278 and the 2-(substitutedphenyl)-1,2,4-triazine-3,5(2H,4H)-diones published in U.S. Pat. No.4,767,760 are excluded therefrom.

Thus, the invention also concerns novel compounds of formula

the N-oxides, the pharmaceutically acceptable addition salts and thestereochemically isomeric forms thereof, wherein p, q, R¹, R², R³ and R⁴are as defined in the compounds of formula (I), provided that thefollowing conditions apply to the variables R^(3a), R^(3b), R^(3c),R^(4a), R^(4b), R^(4c), R¹ and R² in the compounds with generalstructure:

a) if R^(3a), R^(3b) are chloro; R^(4a) is 4-chloro; and R¹, R^(3c),R^(4b) and R^(4c) are hydrogen; then R² is other than aminocarbonyl,carboxyl, chlorocarbonyl, 1-piperidinylcarbonyl, methoxycarbonyl,methylaminocarbonyl, 1-pyrrolidinylcarbonyl,4-methyl-1-piperazinylcarbonyl, methylcarbonyl, NH₂—C(═S)—,phenylcarbonyl; and

b) if R^(3a) is chloro; R^(4a) is 4-chloro; and R¹, R^(3b), R^(3c),R^(4b) and R^(4c) are hydrogen; then R² is other than aminocarbonyl,carboxyl, NH₂—C(═S)—, chlorocarbonyl, methylaminocarbonyl,(4-methylcarbonyl-1-piperazinyl)carbonyl,(4-phenylmethyl-1-piperazinyl)carbonyl or methyloxycarbonyl; and

c) if the combination of R¹, R^(3a), R^(3b), R^(3c), R^(4a), R^(4b) andR^(4c) is one of the following

R¹ R^(3a) R^(3b) R^(3c) R^(4a) R^(4b) R^(4c) 4-chlorophenyl Cl H H H4-Cl H 1-propyl Cl H H H 4-Cl H 1-butyl Cl H H H 4-Cl H CH₃ Cl H H H4-Cl H CH₃ H H H H 4-H H CH₃ H Cl H H 4-F H CH₃ CF₃ H H H 4-Cl H CH₃ ClH H 3-CF₃ 4-Cl H CH₃ Cl Cl H H 4-Cl H CH₃ Cl CH₃ H H 4-Cl H CH₃ F H H H4-F H H Cl CH₃ H H 4-Cl H H Cl H H H 4-F H H Cl H H H 4-CH₃ H H Cl Cl HH 4-F H H Cl CH₃ H H 4-F H H CH₃ CH₃ H H 4-F H H CH₃ CH₃ H H 4-Cl H H ClCl H H 4-Cl H H Cl H H H 4-Cl H H Cl H H 2-Cl 4-Cl H H Cl H H 2-Cl 4-Cl6-Cl H Cl H H H 4-Br H H Cl Cl H H 4-Br H H Cl Cl H H 4-CH₃C(═O)O H H ClCl H H 4-OH H H OH H H H 4-Cl H H Cl H H H 4-CH₃S H H Cl Cl H H 4-CH₃S HH CH₃ CH₃ H H 4-CH₃S H H Cl H H 3-CH₃ 4-CH₃S H H Cl Cl H 3-CH₃ 4-CH₃S HH Cl H H H 4-CH₃SO H H Cl Cl H H 4-CH₃SO H H Cl H H H 4-CH₃S(O)₂ H H ClCl H H 4-CH₃S(O)₂ H H Cl H H H 4-SH H H Cl Cl H H 4-SH H CH₃ Cl H CH₃4-Cl H H H H H OCH₃ 4-Cl H H

then R² is other than cyano.

As used in the foregoing definitions and hereinafter, halo is generic tofluoro, chloro, bromo and iodo; C₃₋₇cycloalkyl is generic tocyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl;C₁₋₄alkyl defines straight and branched chain saturated hydrocarbonradicals having from 1 to 4 carbon atoms such as, for example, methyl,ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylethyland the like; C₁₋₆alkyl is meant to include C₁₋₄alkyl and the higherhomologues thereof having 5 or 6 carbon atoms such as, for example,pentyl, 2-methylbutyl, hexyl, 2-methylpentyl and the like; haloC₁₋₆alkylis defined as polyhalosubstituted C₁₋₆alkyl, in particular C₁₋₆alkylsubstituted with 1 to 6 halogen atoms, more in particular difluoro- ortrifluoromethyl.

Het is meant to include all the possible isomeric forms of theheterocycles mentioned in the definition of Het, for instance, pyrrolylincludes 2H-pyrrolyl; triazolyl includes 1,2,4-triazolyl and1,3,4-triazolyl; oxadiazolyl includes 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl and 1,3,4 oxadiazolyl; thiadiazolylincludes 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl and1,3,4 thiadiazolyl; pyranyl includes 2H-pyranyl and 4H-pyranyl;thiazolopyridinyl includes thiazolo[5,4-b]pyridinyl,thiazolo[5,4-c]pyridinyl, thiazolo[5,4-d]pyridinyl andthiazolo[5,4-e]pyridinyl.

The heterocycles represented by Het may be attached to the remainder ofthe molecule of formula (I) through any ring carbon or heteroatom asappropriate. Thus, for example, when the heterocycle is imidazolyl, itmay be a 1-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl; whenit is triazolyl, it may be 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl,1,2,4-triazol-5-yl, 1,3,4-triazol-1-yl and 1,3,4-triazol-2-yl; when itis benzthiazolyl, it may be 2-benzthiazolyl, 4-benzthiazolyl,5-benzthiazolyl, 6-benzthiazolyl and 7-benzthiazolyl; when it isthiazolopyridinyl, it may be thiazolo[5,4-b]pyridin-2-yl,thiazolo[5,4-b]pyridin-4-yl, thiazolo[5,4-b]pyridin-5-yl,thiazolo[5,4-b]pyridin-6-yl, thiazolo[5,4-c]pyridin-2-yl,thiazolo[5,4-c]pyridin-4-yl, thiazolo[5,4-c]pyridin-5-yl,thiazolo[5,4-c]pyridin-7-yl, thiazolo[5,4-d]pyridin-2-yl,thiazolo[5,4-d]pyridin-4-yl, thiazolo[5,4-d]pyridin-6-yl,thiazolo[5,4-d]pyridin-7-yl, thiazolo[5,4-e]pyridin-2-yl,thiazolo[5,4-e]pyridin-5-yl, thiazolo[5,4-e]pyridin-6-yl andthiazolo[5,4-e]pyridin-7-yl.

The pharmaceutically acceptable addition salts as mentioned hereinaboveare meant to comprise the therapeutically active non-toxic acid additionsalt forms which the compounds of formula (I) are able to form. Thelatter can conveniently be obtained by treating the base form with suchappropriate acids as inorganic acids, for example, hydrohalic acids,e.g. hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid;phosphoric acid and the like; or organic acids, for example, acetic,propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic,ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic,(E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic,2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic,benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic,2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids.Conversely the salt form can be converted by treatment with alkali intothe free base form.

The compounds of formula (I) containing acidic protons may be convertedinto their therapeutically active non-toxic metal or amine addition saltforms by treatment with appropriate organic and inorganic bases.Appropriate base salt forms comprise, for example, the ammonium salts,the alkali and earth alkaline metal salts, e.g. the lithium, sodium,potassium, magnesium, calcium salts and the like, salts with organicbases, e.g. the benzathine, N-methyl-D-glucamine,2-amino-2-(hydroxymethyl)-1,3-propanediol, hydrabamine salts, and saltswith amino acids such as, for example, arginine, lysine and the like.Conversely the salt form can be converted by treatment with acid intothe free acid form.

The term addition salt also comprises the hydrates and solvent additionforms which the compounds of formula (I) are able to form. Examples ofsuch forms are e.g. hydrates, alcoholates and the like.

The N-oxide forms of the present compounds are meant to comprise thecompounds of formula (I) wherein one or several nitrogen atoms areoxidized to the so-called N-oxide.

Some of the compounds of formula (I) may also exist in their tautomericforms. Such forms although not explicitly indicated in the above formulaare intended to be included within the scope of the present invention.

The term “stereochemically isomeric forms” as used hereinbefore definesall the possible stereoisomeric forms in which the compounds of formula(I) can exist. Unless otherwise mentioned or indicated, the chemicaldesignation of compounds denotes the mixture of all possiblestereochemically isomeric forms, said mixtures containing alldiastereomers and enantiomers of the basic molecular structure. More inparticular, stereogenic centers may have the R- or S-configuration, usedherein in accordance with Chemical Abstracts nomenclature.Stereochemically isomeric forms of the compounds of formula (I) areobviously intended to be embraced within the scope of this invention.

The compounds of formula (I) and some of the intermediates in thepresent invention contain one or more asymmetric carbon atoms. The pureand mixed stereochemically isomeric forms of the compounds of formula(I) are intended to be embraced within the scope of the presentinvention.

Whenever used hereinafter, the term “compounds of formula (I)” is meantto also include their N-oxide forms, their pharmaceutically acceptableaddition salts, and their stereochemically isomeric forms.

The numbering of the phenyl ring bearing substituent R⁴ is givenhereinbelow and is used herein as such when indicating the position ofthe R⁴ substituents on said phenyl ring, unless otherwise indicated.

The carbon atom bearing the two phenyl rings and the R¹ and R²substituents will be referred herein as the central chiral carbon atom.

A suitable subgroup consists of those compounds of formula (I) or (I′)wherein Het is other than pyrrolidinyl.

A special group of compounds are those compounds of formula (I) or (I′)wherein R² is a radical of formula —C(═X)—Y—R⁵ wherein Y is a directbond and R⁵ is Het.

Another special group of compounds are those compounds of formula (I) or(I′) wherein R¹ is mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, mercapto,C₁₋₆alkylthio or C₁₋₆alkyl substituted with mono- or di(C₁₋₆alkyl)amino,C₁₋₆alkyloxy or Het.

An interesting group of compounds are those compounds of formula (I) or(I′) wherein the 6-azauracil moiety is connected to the phenyl ring inthe para or meta position relative to the central chiral carbon atom,particularly in the para position.

Another interesting group of compounds are those compounds of formula(I) or (I′) wherein R² is cyano.

Still another interesting group of compounds are those compounds offormula (1) or (I′) wherein R² is a radical of formula —C(═X)—Y—R⁵wherein R⁵ is hydrogen, C₁₋₆alkyl or aryl while Y is O, S or NR⁶ whereinR⁶ is hydrogen or C₁₋₆alkyloxy; or R⁵ is aryl, C₁₋₆alkyl, halo, Het orC₁₋₆alkyl substituted with aryl while Y is a direct bond. Suitably, Hetis optionally substituted piperazinyl, imidazolyl, thiazolyl orbenzothiazolyl.

Yet another interesting group of compounds are those compounds offormula (I) or (I′) wherein R¹ is hydrogen, aryl, C₁₋₆alkyl, mono- ordi(C₁₋₆alkyl)aminoC₁₋₆alkyl or HetC₁₋₆alkyl.

Particular compounds are those compounds of formula (I) or (I′) whereinR³ and R⁴ each independently are halo, haloC₁₋₆alkyl, hydroxy,C₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylcarbonyloxy or aryl, more inparticular, bromo, chloro, fluoro, trifluoromethyl, methyl, hydroxy,methoxy, methylcarbonyloxy or phenyl.

Other particular compounds are those compounds of formula (I) or (I′)wherein p is 0, 1 or 2, and q is 0, 1, 2 or 3, more in particular, p andq each independently are 1 or 2.

Preferred compounds are those compounds of formula (I) or (I′) wherein qis 1 or 2 and one R⁴ substituent, preferably selected from chloro,fluoro, methyl, hydroxy, methoxy, methylcarbonyloxy and phenyl, is inthe 4 position.

Other preferred compounds are those compounds of formula (I) or (I′)wherein p is 1 or 2 and the one or two R³ substituents, preferablyselected from bromo, chloro, methyl, methoxy or trifluoromethyl, are inthe ortho position relative to the central chiral carbon atom.

More preferred compounds are those compounds of formula (I) or (I′)wherein the 6-azauracil moiety is in the para position relative to thecentral chiral carbon atom; p is 1 or 2 and one R³ substituent is chloropositioned ortho relative to the central chiral carbon atom; q is 1 or 2and one R⁴ substituent is chloro in the 4 position.

Particularly preferred compounds are those compounds as describedhereinabove as more preferred compounds wherein R² is cyano or a radicalof formula —C(═X)—Y—R⁵ wherein Y is a direct bond.

The compounds of the present invention can generally be prepared asdescribed in U.S. Pat. Nos. 4,631,278 and 4,767,760.

In particular, the compounds of formula (I′) can be prepared bycyclizing an intermediate of formula (II) and eliminating the group Efrom the thus obtained dione of formula (III).

A suitable way of eliminating group E, which is for example a carboxylgroup, may be reacting intermediate of formula (III) with mercaptoaceticacid or a functional derivative thereof.

The compounds of formula (I′) may also be prepared by eliminating theprotective group P in the intermediates of formula (IV).

A suitable way of eliminating group P, which is for example aalkyloxyalkyloxyalkyl moiety, may be reacting intermediate of formula(IV) with a acid or an acid mixture such as hydrochloric acid, aceticacid or a mixture thereof. Alternatively, the protective group P may beremoved by reacting an intermediate of formula (IV) with a suitablereagent such as, for example, boron tribromide, in a reaction-inertsolvent such as, for example, dichloromethane.

The compounds of formula (I′) wherein R² is cyano, said compounds beingrepresented by formula (I′-a), can be prepared by converting thehydroxyl function of an intermediate of formula (V) into a suitableleaving group W such as, for example, a halogen or a sulfonyloxy group,and subsequently converting said leaving group W in the thus formedintermediate of formula (VI) into a nitrile function.

The compounds of formula (I′) wherein R¹ is hydrogen and R² is cyano,said compounds being represented by formula (I′-a-1), can be prepared byreacting the carbonyl group in the intermediates of formula (VII) with asuitable reagent such as, for example,1-[(isocyanomethyl)sulfonyl]-4-methylbenzene or a functional derivativethereof.

The compounds of formula (I) can be converted into each other followingart-known procedures of functional group transformation and aredescribed in U.S. Pat. No. 4,767,760, Some interesting grouptransformation reactions described therein are mentioned hereinafter.

In order to simplify the structural representation of the compounds offormula (I′), the group

will hereinafter be represented by the symbol D.

The compounds of formula (I′-a) may be partially or completelyhydrolyzed, thus yielding compounds of formula (I′) wherein R² is anaminocarbonyl or a carboxyl group, the former being represented byformula (I′-f), the latter by (I′-b). The compounds of formula (I′-f)can further be hydrolized to compounds of formula (I′-b).

The compounds of formula (I′-a) may also be converted to compounds offormula (I′-g) wherein R² is an aminothioxomethyl group.

The acids of formula (I′-b) can be converted to the correspondingacylhalides of formula (I′-c). Said acylhalides of formula (I′-c) canfurther be derivatized using HN(R⁵)(R⁶) to the corresponding amides offormula (I′-d) which in turn may further be reacted to a heteroarylketone of formula (I′-e) using a suitable metal alkyl such as, forexample, butyl lithium, in a reaction-inert solvens such as, forexample, tetrahydrofuran, hexane, diethylether or a mixture thereof. Thelatter reaction may conveniently be performed under an inert atmospheresuch as, for example, oxygen-free nitrogen, and at a low reactiontemperature, preferably at about −70° C. The acylhalides of formula(I′-c) can also be reacted with a Grignard reagent, e.g. RMgX, wherein Xis a suitable counter ion such as a halogen, and R is C₃₋₇cycloalkyl orC₁₋₆alkyl optionally substituted with aryl or Het, thus obtainingintermediates of formula (I′-h).

In addition, the compounds of formula (I′) may be converted to thecorresponding N-oxide forms following art-known procedures forconverting a trivalent nitrogen into its N-oxide form. Said N-oxidationreaction may generally be carried out by reacting the starting materialof formula (I) with an appropriate organic or inorganic peroxide.Appropriate inorganic peroxides comprise, for example, hydrogenperoxide, alkali metal or earth alkaline metal peroxides, e.g. sodiumperoxide, potassium peroxide; appropriate organic peroxides may compriseperoxy acids such as, for example, benzenecarboperoxoic acid or halosubstituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoicacid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides,e.g. tert-butyl hydroperoxide. Suitable solvents are, for example,water, lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g.toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g.dichloromethane, and mixtures of such solvents.

Pure stereochemically isomeric forms of the compounds of formula (I′)may be obtained by the application of art-known procedures.Diastereomers may be separated by physical methods such as selectivecrystallization and chromatographic techniques, e.g. counter-currentdistribution, liquid chromatography and the like.

The compounds of formula (I′) as prepared in the hereinabove describedprocesses are generally racemic mixtures of enantiomers which can beseparated from one another following art-known resolution procedures.The racemic compounds of formula (I′) which are sufficiently basic oracidic may be converted into the corresponding diastereomeric salt formsby reaction with a suitable chiral acid respectively with a suitablechiral base. Said diastereomeric salt forms are subsequently separated,for example, by selective or fractional crystallization and theenantiomers are liberated therefrom by alkali or acid. An alternativemanner of separating the enantiomeric forms of the compounds of formula(I′) involves liquid chromatography using a chiral stationary phase.Said pure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound will be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

An alternative manner of separating the enantiomeric forms of thecompounds of formula (I) and intermediates involves liquidchromatography, in particular liquid chromatography using a chiralstationary phase.

A number of intermediates and starting materials in the foregoingpreparations are commercially available or are known compounds which maybe prepared according to art-known methodologies of preparing said orsimilar intermediates. In particular, the preparation of theintermediates of formula (II), (IV), (V) and (VII) are described in U.S.Pat. Nos. 4,631,278, 4,767,760, 3,883,527 and Carroll et al. in J. Med.Chem. 1983, 26, 96-100.

IL-5, also known as eosinophil differentiating factor (EDF) oreosinophil colony stimulating factor (Eo-CSF), is a major survival anddifferentiation factor for eosinophils and basophils and thereforethought to be a key player in eosinophil infiltration into tissues.There is ample evidence that eosinophil influx is an importantpathogenic event in bronchial asthma and allergic diseases such as,cheilitis, irritable bowel disease, eczema, urticaria, vasculitis,vulvitis, winterfeet, atopic dermatitis, pollinosis, allergic rhinitisand allergic conjunctivitis; and other inflammatory diseases, such aseosinophilic syndrome, allergic angiitis, eosinophilic fasciitis,eosinophilic pneumonia, PIE syndrome, idiopathic eosinophilia,eosinophilic myalgia, Crohn's disease, ulcerative colitis and the likediseases.

The present compounds also inhibit the production of other chemokinessuch as monocyte chemotactic protein-1 and -3 (MCP-1 and MCP-3). MCP-1is known to attract both T-cells, in which IL-5 production mainlyoccurs, and monocytes, which are known to act synergetically witheosinophils (Carr et al., 1994, Immunology, 91, 3652-3656). MCP-3 alsoplays a primary role in allergic inflammation as it is known to mobilizeand activate basophil and eosinophil leukocytes (Baggiolini et al.,1994, immunology Today, 15(3), 127-133).

The present compounds have no or little effect on the production ofother chemokines such as IL-1, IL-2, IL-3, IL-4, IL-6, IL-10,γ-interferon (IFN-γ) and granulocyte-macrophage colony stimulatingfactor (GM-CSF) indicating that the present IL-5 inhibitors do not actas broad-spectrum immunosuppressives.

The selective chemokine inhibitory effect of the present compounds canbe demonstrated by in vitro chemokine measurements in human blood ofwhich the test results for IL-5 are presented in the experimental parthereinafter. In vivo observations such as the inhibition of eosinophiliain mouse ear, the inhibition of blood eosinophilia in the Ascaris mousemodel; the reduction of serum IL-5 protein production and splenic IL-5mRNA expression induced by anti-CD3 antibody in mice and the inhibitionof allergen- or Sephadex-induced pulmonary influx of eosinophils inguinea-pig are indicative for the usefulness of the present compounds inthe treatment of eosinophil-dependent inflammatory diseases.

The present inhibitors of IL-5 production are orally active compounds.

In view of the above pharmacological properties, the present compoundscan be used in the manufacture of a medicament for treatingeosinophil-dependent inflammatory diseases as mentioned hereinabove, inparticular bronchial asthma, atopic dermatitis, allergic rhinitis andallergic conjunctivitis. The present invention also involves two groupsof novel compounds for use as a medicine. One of said groups consists ofthose compounds of formula (I′) wherein R¹ is mono- ordi(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, mercapto, C₁₋₆alkylthio or C₁₋₆alkylsubstituted with mono- or di(C₁₋₆alkyl)amino, C₁₋₆alkyloxy or Het, theother group consists of those compounds of formula (I′) wherein R² is aradical of formula —C(═X)—Y—R⁵ wherein Y is a direct bond and R⁵ is Het.

In view of the utility of the compounds of formula (I), there isprovided a method of treating warm-blooded animals, including humans,suffering from eosinophil-dependent inflammatory diseases, in particularbronchial asthma, atopic dermatitis, allergic rhinitis and allergicconjunctivitis. Said method comprises the systemic or topicaladministration of an effective amount of a compound of formula (I), aN-oxide form, a pharmaceutically acceptable addition salt or a possiblestereoisomeric form thereof, to warm-blooded animals, including humans.

The present invention also provides compositions for treatingeosinophil-dependent inflammatory diseases comprising a therapeuticallyeffective amount of a compound of formula (I) and a pharmaceuticallyacceptable carrier or diluent together with instructions for the usethereof for the treatment of an eosinophil-dependent inflammatorydisease.

In particular, the present invention provides compositions for treatingeosinophil-dependent inflammatory diseases comprising a therapeuticallyeffective amount of a compound of formula (I′) wherein R² is a radicalof formula —C(═X)—Y—R⁵ wherein Y is a direct bond and R⁵ is Het or acompound of formula (I′) wherein R¹ is mono- ordi(C₁₋₆alkyl)aminoC₁₋₆alkyloxy, mercapto, C₁₋₆alkylthio or C₁₋₆alkylsubstituted with mono- or di(C₁₋₆alkyl)amino, C₁₋₆alkyloxy or Het, and apharmaceutically acceptable carrier or diluent.

To prepare the aforementioned pharmaceutical compositions, atherapeutically effective amount of the particular compound, optionallyin addition salt form, as the active ingredient is combined in intimateadmixture with a pharmaceutically acceptable carrier, which may take awide variety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirably inunitary dosage form suitable, preferably, for systemic administrationsuch as oral, percutaneous, or parenteral administration; or topicaladministration such as via inhalation, a nose spray, eye drops or via acream, gel, shampoo or the like. For example, in preparing thecompositions in oral dosage form, any of the usual pharmaceutical mediamay be employed, such as, for example, water, glycols, oils, alcoholsand the like in the case of oral liquid preparations such assuspensions, syrups, elixirs and solutions; or solid carriers such asstarches, sugars, kaolin, lubricants, binders, disintegrating agents andthe like in the case of powders, pills, capsules and tablets. Because oftheir ease in administration, tablets and capsules represent the mostadvantageous oral dosage unit form, in which case solid pharmaceuticalcarriers are obviously employed. For parenteral compositions, thecarrier will usually comprise sterile water, at least in large part,though other ingredients, for example, to aid solubility, may beincluded. Injectable solutions, for example, may be prepared in whichthe carrier comprises saline solution, glucose solution or a mixture ofsaline and glucose solution. Injectable solutions containing compoundsof formula (I) may be formulated in an oil for prolonged action.Appropriate oils for this purpose are, for example, peanut oil, sesameoil, cottonseed oil, corn oil, soy bean oil, synthetic glycerol estersof long chain fatty acids and mixtures of these and other oils.Injectable suspensions may also be prepared in which case appropriateliquid carriers, suspending agents and the like may be employed. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewettable agent, optionally combined with suitable additives of anynature in minor proportions, which additives do not cause anysignificant deleterious effects on the skin. Said additives mayfacilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as a spot-onor as an ointment. As appropriate compositions for topical applicationthere may be cited all compositions usually employed for topicallyadministering drugs e.g. creams, gellies, dressings, shampoos,tinctures, pastes, ointments, salves, powders and the like. Applicationof said compositions may be by aerosol, e.g. with a propellent such asnitrogen, carbon dioxide, a freon, or without a propellent such as apump spray, drops, lotions, or a semisolid such as a thickenedcomposition which can be applied by a swab. In particular, semisolidcompositions such as salves, creams, gellies, ointments and the likewill conveniently be used.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

Preferred compositions are those compositions containing a novelcompound of formula (I′) wherein R² is a radical of formula —C(═X)—Y—R⁵wherein Y is a direct bond and R⁵ is Het, or a novel compound of formula(I′) wherein R¹ is mono- or di(C₁₋₆alkyl)amino-C₁₋₆alkyloxy, mercapto,C₁₋₆alkylthio or C₁₋₆alkyl substituted with mono- or di(C₁₋₆alkyl)amino,C₁₋₆alkyloxy or Het, and are in dosage unit form, comprising per dosageunit an effective quantity of active ingredient in admixture withsuitable carriers.

In order to enhance the solubility and/or the stability of the compoundsof formula (I) in pharmaceutical compositions, it can be advantageous toemploy α-, β- or γ-cyclodextrins or their derivatives. Also co-solventssuch as alcohols may improve the solubility and/or the stability of thecompounds of formula (I) in pharmaceutical compositions. In thepreparation of aqueous compositions, addition salts of the subjectcompounds are obviously more suitable due to their increased watersolubility.

Appropriate cyclodextrins are α-, β-, γ-cyclodextrins or ethers andmixed ethers thereof wherein one or more of the hydroxy groups of theanhydroglucose units of the cyclodextrin are substituted with C₁₋₆alkyl,particularly methyl, ethyl or isopropyl, e.g. randomly methylated β-CD;hydroxyC₁₋₆alkyl, particularly hydroxyethyl, hydroxypropyl orhydroxybutyl; carboxyC₁₋₆alkyl, particularly carboxymethyl orcarboxyethyl; C₁₋₆alkylcarbonyl, particularly acetyl;C₁₋₆alkyloxycarbonylC₁₋₆alkyl or carboxy-C₁₋₆alkyloxyC₁₋₆alkyl,particularly carboxymethoxypropyl or carboxyethoxypropyl;C₁₋₆alkylcarbonyloxyC₁₋₆alkyl, particularly 2-acetyloxypropyl.Especially noteworthy as complexants and/or solubilizers are β-CD,randomly methylated β-CD, 2,6-dimethyl-β-CD, 2-hydroxyethyl-β-CD,2-hydroxyethyl-γ-CD, 2-hydroxypropyl-γ-CD and(2-carboxymethoxy)propyl-β-CD, and in particular 2-hydroxypropyl-β-CD(2-HP-β-CD).

The term mixed ether denotes cyclodextrin derivatives wherein at leasttwo cyclodextrin hydroxy groups are etherified with different groupssuch as, for example, hydroxy-propyl and hydroxyethyl.

Due to their high degree of selectivity as IL-5 inhibitors, thecompounds of formula (I) as defined above, are also useful to mark oridentify receptors. To this purpose, the compounds of the presentinvention need to be labelled, in particular by replacing, partially orcompletely, one or more atoms in the molecule by their radioactiveisotopes. Examples of interesting labelled compounds are those compoundshaving at least one halo which is a radioactive isotope of iodine,bromine or fluorine; or those compounds having at least one ¹¹C-atom ortritium atom.

One particular group consists of those compounds of formula (I) whereinR³ and/or R⁴ are a radioactive halogen atom. In principle, any compoundof formula (I) containing a halogen atom is prone for radiolabelling byreplacing the halogen atom by a suitable isotope. Suitable halogenradioisotopes to this purpose are radioactive iodides, e.g. ¹²²I, ¹²³I,¹²⁵I, ¹³¹I; radioactive bromides, e.g. ⁷⁵Br, ⁷⁶Br, ⁷⁷Br and ⁸²Br, andradioactive fluorides, e.g. ¹⁸F. The introduction of a radioactivehalogen atom can be performed by a suitable exchange reaction or byusing any one of the procedures as described hereinabove to preparehalogen derivatives of formula (I).

Another interesting form of radiolabelling is by substituting a carbonatom by a ¹¹C-atom or the substitution of a hydrogen atom by a tritiumatom.

Hence, said radiolabelled compounds of formula (I) can be used in aprocess of specifically marking receptor sites in biological material.Said process comprises the steps of (a) radiolabelling a compound offormula (I), (b) administering this radiolabelled compound to biologicalmaterial and subsequently (c) detecting the emissions from theradiolabelled compound. The term biological material is meant tocomprise every kind of material which has a biological origin. More inparticular this term refers to tissue samples, plasma or body fluids butalso to animals, specially warm-blooded animals, or parts of animalssuch as organs.

The radiolabelled compounds of formula (I) are also useful as agents forscreening whether a test compound has the ability to occupy or bind to aparticular receptor site. The degree to which a test compound willdisplace a compound of formula (I) from such a particular receptor sitewill show the test compound ability as either an agonist, an antagonistor a mixed agonist/antagonist of said receptor.

When used in in vivo assays, the radiolabelled compounds areadministered in an appropriate composition to an animal and the locationof said radiolabelled compounds is detected using imaging techniques,such as, for instance, Single Photon Emission Computerized Tomography(SPECT) or Positron Emission Tomography (PET) and the like. In thismanner the distribution of the particular receptor sites throughout thebody can be detected and organs containing said receptor sites can bevisualized by the imaging techniques mentioned hereinabove. This processof imaging an organ by administering a radiolabelled compound of formula(I) and detecting the emissions from the radioactive compound alsoconstitutes a part of the present invention.

A suitable therapeutically effective daily amount would be from 0.01mg/kg to 50 mg/kg body weight, in particular from 0.05 mg/kg to 10 mg/kgbody weight. A method of treatment may also include administering theactive ingredient on a regimen of between two or four intakes per day.

EXPERIMENTAL PART

A. Preparation of the Intermediate Compounds

Herinafter, “THF” stands for tetrahydrofuran, “RT” stands for roomtemperature, “DIPE” stands for diisopropylether, “EtOAc” stands forethylacetate and “DMF” stands for N,N-dimethylformamide.

Example A.1

a) A solution of 4-chloro-3-(trifluoromethyl)benzeneacetonitrile (0.114mol) in THF (100 ml) was added dropwise at RT to a solution of1,2,3-trichloro-5-nitrobenzene (0.114 mol) andN,N,N-triethylbenzenemethanaminium chloride (3 g) in NaOH (150 ml) andTHF (100 ml). The mixture was stirred at RT for 2 hours, then poured outon ice, acidified with a concentrated HCl solution and extracted withCH₂Cl₂. The organic layer was separated, dried, filtered and the solventwas evaporated. The residue was crystallized from DIPE. The precipitatewas filtered off and dried, yielding 40.4 g (86.5%) of(±)-2,6-dichloro-α-[4-chloro-3-(trifluoromethyl)phenyl]-4-nitrobenzene-acetonitrile(interm. 1).

b) A mixture of (3,4-dichlorophenyl)acetonitrile (0.149 mol) in DMF (100ml) was stirred at 0° C. under N₂ flow. Sodium hydride (0.223 mol) wasadded portionwise. The mixture was stirred at 0° C. under N₂ flow for 1hour. A mixture of, 2-methoxy-1,3-dimethyl-5-nitrobenzene (0.149 mol) inDMF (100 ml) was added dropwise at 0° C. under N₂ flow. The mixture wasstirred at RT for 6 hours, then cooled, hydrolized with H₂O and with HCl3N and extracted with EtOAc. The organic layer was separated, washedseveral times with H₂O, dried, filtered and the solvent was evaporated.The residue was crystallized from DIPE. The precipitate was filtered offand dried, yielding 43.4 g (87%) of(±)-α-(3,4-dichlorophenyl)-2,6-dimethyl-4-nitrobenzeneacetonitrile(interm. 48).

c) A solution of intermediate 1 (0.0466 mol), iodomethane (0.0606 mol),KOH (0.1864 mol) and N,N,N-triethylbenzenemethanaminium chloride (0.0466mol) in toluene (200 ml) was stirred at 50° C. for 2 hours. The mixturewas poured out into water, acidified with HCl (3N) and extracted withCH₂Cl₂. The organic layer was separated, dried, filtered and the solventwas evaporated. The residue was purified by column chromatography oversilica gel (eluent: cyclohexane/EtOAc 90/10). The pure fractions werecollected and the solvent was evaporated, yielding 11 g (55%) of(±)-2,6-dichloro-α-[4-chloro-3-(trifluoromethyl)phenyl]-(X-methyl-4-nitrobenzene-acetonitrile(interm. 2)

Example A.2

a) A mixture of intermediate 2 (0.0259 mol) in methanol (200 ml) washydrogenated at 40° C. overnight with platinum-on-activated carbon (1%;1 g) as a catalyst in the presence of thiophene (10% in ethanol; 1 ml).After uptake of hydrogen, the catalyst was filtered through celite,washed with CH₃OH and the filtrate was evaporated, yielding 10 g (98%)of(±)-4-amino-2,6-dichloro-α-[4-chloro-3-(trifluoromethyl)-phenyl]-α-methylbenzeneacetonitrile(interm. 3).

b) A mixture of intermediate 1 (0.138 mol) in methanol (300 ml) washydrogenated at RT under a 3 bar pressure for 1 hour with Raney Nickel(50 g) as a catalyst in the presence of a 10% thiophene solution inethanol (5 ml). After uptake of hydrogen, the catalyst was filteredthrough celite, washed with CH₃OH and CH₂Cl₂ and the filtrate wasevaporated, yielding 49.5 g (94%) of(±)-4-amino-2,6-dichloro-α-[4-chloro-3-(trifluoromethyl)phenyl]benzeneacetonitrile(interm. 46).

c) A solution of 15% TiCl₃ in water (0.13 mol) was added dropwise at RTto a solution of(±)-2,6-dibromo-α-(4-chlorophenyl)-4-nitrobenzeneacetonitrile (0.026mol) in THF (200 ml). The mixture was stirred at RT for 2 hours, pouredout into H₂O and extracted with CH₂Cl₂. The organic layer was separated,washed with H₂O and with K₂CO₃ 10%, dried, filtered and the solvent wasevaporated. A part of this residue (2 g) was crystallized from diethylether. The precipitate was filtered off and dried, yielding 1.3 g(±)-4-amino-2,6-dibromo-α-(4-chlorophenyl)benzeneacetonitrile (interm.47).

Example A.3

a) A solution of sodium nitrite (0.0243 mol) in water (10 ml) was addeddropwise at 5° C. to a solution of intermediate 3 (0.0243 mol) in aceticacid (75 ml) and concentrated HCl (20 ml). The mixture was stirred at 0°C. for 35 minutes and then added dropwise to a solution of ethyl(cyanoacetyl)carbamoate (0.0326 mol) and sodium acetate (112 g) in icewater (1300 ml). The mixture was stirred at 0° C. for 45 minutes. Theprecipitate was filtered off, washed with water and taken up in CH₂Cl₂.The organic layer was separated, washed with water, dried, filtered andthe solvent was evaporated, yielding 15.2 g (±)-ethyl2-cyano-2-[[3,5-dichloro-4-[1-[4-chloro-3-(trifluoromethyl)phenyl]-1-cyanoethyl]phenyl]hydrazono]-1-oxoethylcarbamate(interm. 4)

b) A mixture of intermediate 4 (0.0271 mol) and potassium acetate(0.0285 mol) in acetic acid (150 ml) was stirred and refluxed for 3hours and then poured out on ice. The precipitate was filtered off,washed with water and taken up in EtOAc. The organic layer wasseparated, washed with water, dried, filtered and the solvent wasevaporated, yielding 12 g (86%) of(±)-2-[3,5-dichloro-4-[1-[4-chloro-3-(trifluoromethyl)phenyl]-1-cyanoethyl]phenyl]-2,3,4,5-tetrahydro-3,5-dioxo-1,2,4-triazine-6-carbonitrile(interm. 5).

c) A mixture of intermediate 5 (0.0223 mol) in HCl (40 ml) and aceticacid (150 ml) was stirred and refluxed for 3 hours and then poured outinto ice water. The precipitate was filtered off, taken up in CH₂Cl₂ andCH₃OH, washed with water, dried, filtered and the solvent wasevaporated, yielding 11.4 g (96%) of(±)-2-[3,5-dichloro-4-[1-[4-chloro-3-trifluoromethyl)phenyl]-1-cyanoethyl]phenyl]-2,3,4,5-tetrahydro-3,5-dioxo-1,2,4-triazine-6-carboxylicacid (interm. 6).

The following intermediates were prepared according to the proceduresdescribed in example A.3.

TABLE 1

Interm. No. R¹ R² R^(3a) R^(3b) R^(3c) R^(4a) R^(4b) R^(4c) R^(4d)  7CH₃ CN Cl H H H Cl Cl H  8 CH₃ CN Cl H H H OCH₃ OCH₃ H  9 CH₃ CN Cl H HH OCH_(3 H) H 10 CH₃ CN Cl H H H Cl OCH₃ H 11 CH₃ CN Cl H CH₃ H Cl CF₃ H12 CH₃ CN Cl H H H Cl OCH₃ H 13 CH₃ CN OCH₃ H H H Cl CF₃ H 14 CH₃ CN ClH H OCH₃ OCH₃ OCH₃ H 15 CH₃ CN Cl Cl H H Cl Cl H 16 CH₃ CN Cl H H H ClCH₃ H 17 CH₃ CN Cl H H H CH₃ OCH₃ H 18 CH₃ CN Cl H H H Cl H Cl 19 CH₃ CNH H H H Cl H Cl 20 CH₃ CN CH₃ H H CF₃ Cl H H 21 CH₃ CN Cl H H H phenyl HH 33 H CN CH₃ CH₃ H H Cl Cl H 34 H CN Cl Cl H H Cl CH₃ H 35 CH₃ CN Cl ClH H Cl F H 36 H CN Cl Cl H H Cl OCH₃ H 37 H CN Br Br H H Cl H H 38 CH₃C(═O)OC₂H₅ Cl Cl H H Cl H H

Example A.4

a) A mixture of(±)-4-chloro-α-[2-chloro-3-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)phenyl]-3-(trifluoromethyl)benzeneacetonitrile(0.00542 mol), 1-(chloromethoxy)-2-methoxyethane (0.006 mol) andtriethylamine (0.0065 mol) in THF (15 ml) was stirred at RT for 2 hours.The mixture was poured out into water and extracted with EtOAc. Theorganic layer was separated, dried, filtered and the solvent wasevaporated, yielding 3.4 g of(±)-4-chloro-α-[2-chloro-3-[4,5-dihydro-4-[(2-methoxyethoxy)methyl]-3,5-dioxo-1,2,4-triazin-2(3H)-yl]phenyl]-3-(trifluoromethyl)benzeneacetonitrile(interm. 22).

(±)-2-chloro-α-(4-chlorophenyl)-4-[4,5-dihydro-4-[(2-methoxyethoxy)methyl]-3,5-dioxo-1,2,4-triazin-2(3H)-yl]benzeneacetonitrilewas prepared in an analogous way (interm. 39).

b) 2-methyl-2-propanol, potassium salt (0.0193 mol) was addedportionwise at 0° C. under N₂ flow to a solution of intermediate 22(0.00642 mol) and iodomethane (0.0321 mol) in DMF (10 ml). The mixturewas stirred at 0° C. for 2 hours, then poured out into ice water andextracted with diethyl ether. The organic layer was separated, washedwith water, dried, filtered and the solvent was evaporated. The residuewas purified by column chromatography over silica gel (eluent:cyclohexane/EtOAc 50/50 to 35/65). The pure fractions were collected andthe solvent was evaporated, yielding 2.07 g (60%) of(±)-4-chloro-α-[2-chloro-3-[4,5-dihydro-4-[(2-methoxyethoxy)methyl]-3,5-dioxo-1,2,4-triazin-2(3H)-yl]phenyl]-α-methyl-3-(trifluoromethyl)benzeneacetonitrile(interm. 23).

(±)-4-chloro-α-[2-chloro-5-[4,5-dihydro-4-[(2-methoxyethoxy)methyl]-3,5-dioxo-1,2,4-triazin-2(3H)-yl]phenyl]-α-methyl-3-(trifluoromethyl)benzeneacetonitrilewas prepared in an analogous way (interm. 24).

Example A.5

a) A solution of 4-bromo-1-chloro-2-(trifluoromethyl)benzene (0.165 mol)in THF (30 ml) was added dropwise under N₂ flow to a suspension of Mg(0.181 mol) and a crystal of I₂ in THF (20 ml). The mixture was stirredat 30-35° C. for 2.5 hours and then cooled to 10° C. The mixture wasadded dropwise at 5° C. under N₂ flow to a solution ofN-(2-chloro-3-formylphenyl)acetamide (0.0788 mol) in THF (500 ml). Themixture was stirred at RT for 3 hours, poured out into ice and NH₄Cl,and extracted with EtOAc. The organic layer was separated, dried,filtered and the solvent was evaporated. The residue was purified bycolumn chromatography (eluent: CH₂Cl₂/CH₃OH 98.5/1.5). The purefractions were collected and the solvent was evaporated, yielding 22.2 g(74%) of(±)-N-[2-chloro-3-[[4-chloro-3-(trifluoromethyl)phenyl]hydroxymethyl]phenyl]acetamide(interm. 25).

b) A mixture of intermediate 25 (0.0587 mol) and manganese(IV) oxide(0.587 mol) in CH₂Cl₂ (400 ml) was stirred at RT for 24 hours andfiltered over celite. The solvent was evaporated, yielding 19.21 g (87%)of N-[2-chloro-3-[4-chloro-3-(trifluoromethyl)benzoyl]phenyl]acetamide(interm. 26).

c) A mixture of intermediate 26 (0.0511 mol) in HCl (6N; 200 ml) wasstirred and refluxed for 5 hours. The mixture was cooled, poured intoice, basified with NH₄OH and extracted with CH₂Cl₂. The organic layerwas dried, filtered and the solvent was evaporated, yielding 17.1 g(100%) of(3-amino-2-chlorophenyl)[4-chloro-3-(trifluoromethyl)phenyl]methanone(interm. 27).

d)2-[2-chloro-3-[4-chloro-3-(trifluoromethyl)benzoyl]phenyl]-2,3,4,5-tetrahydro-3,5-dioxo-1,2,4-triazine-6-carboxylicacid was prepared according to the procedures described in exampleA2.a), A2.b) and A2.c) (intern. 28).

e) A mixture of intermediate 28 (0.0207 mol) in mercaptoacetic acid (10ml) was heated at 160° C. for 3 hours. The solution was cooled andpoured on ice. EtOAc was added and the mixture was basified with NaHCO₃.The organic layer was separated, dried, filtered and the solvent wasevaporated. 0.8 g of the residue was crystallized from 2-propanol/DIPE.The precipitate was filtered off and dried, yielding 0.5 g (93%) of2-[2-chloro-3-[4-chloro-3-(trifluoromethyl)benzoyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione(interm. 29).

2-[4-chloro-3-[4-chloro-3-(trifluoromethyl)benzoyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dionewas prepared according to the procedures described in example A5.a)through A5.e) (interm. 30).

Example A.6

a) A mixture of2-[4-(4-chlorobenzoyl)phenyl]-1,2,4-triazine-3,5-(2H,4H)-dione (0.05mol), ethanol (150 ml), water (150 ml) and NaOH (50%; 10 ml) was stirredat 10° C. A mixture of NaBH₄ (0.05 mol), water (50 ml) and NaOH (50%; 2ml) was added dropwise during 15 minutes. After stirring for 3 hours,300 ml ice was added. The mixture was acidified with concentrated HCl.The product was extracted with CHCl₃, yielding 5.8 g of2-[4-[(4-chlorophenyl)hydroxymethyl]phenyl]-1,2,4-triazine-3,5-(2H,4H)-dione(intern. 31). The organic layer was dried, filtered and evaporated. Theresidue was crystallized with 2-propanol. The product was filtered off,washed with 2,2′-oxybispropane and dried, yielding a second fraction of5.5 g of intermediate 31.

b) A mixture of intermediate 31 (0.053 mol), thionylchloride (50 ml) andCHCl₃ (200 ml) was stirred and refluxed for 2 hours. The solvent wasevaporated. After the addition of toluene, the solvent was evaporatedagain, yielding 18.4 g of2-[4-[chloro(4-chlorophenyl)methyl]phenyl]-1,2,4-triazine-3,5-(2H,4H)-dione(interm. 32).

Example A.7

a) NaH (0.042 mol; 80% in oil) was added portionwise at 10° C. under N₂flow to a solution of intermediate 39 (0.0325 mol) in DMF (90 ml). Themixture was stirred for 15 minutes. A solution of1-bromo-3-chloro-propane (0.065 mol) in DMF (20 ml) was added dropwise.The mixture was stirred at RT for 24 hours. H₂O (250 ml) was added. Themixture was filtered over celite, washed with H₂O and extracted withCH₂Cl₂. The organic layer was separated, dried, filtered and the solventwas evaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/EtOAc 85/15). The pure fractions werecollected and the solvent was evaporated, yielding 7.5 g (43%) of(±)-2-chloro-α-(4-chlorophenyl)-α-(3-chloropropyl)-4-[4,5-dihydro-4-[(2-methoxyethoxy)methyl]-3,5-dioxo-1,2,4-triazin-2(3H)-yl]benzeneacetonitrile(interm. 40).

b) A mixture of intermediate 40 (0.0132 mol), dimethylamine (0.066 mol)and potassium carbonate (0.066 mol) in acetonitrile (100 ml) was stirredand refluxed for 12 hours and then allowed to cool to RT. H₂O was added.The mixture was extracted with CH₂Cl₂. The organic layer was separated,dried, filtered and the solvent was evaporated. The residue was purifiedby column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH97.5/2.5/0.5). The pure fractions were collected and the solvent wasevaporated, yielding 2.5 g (35%) of(±)-2-chloro-α-(4-chlorophenyl)-4-[4,5-dihydro-4-[(2-methoxyethoxy)methyl]-3,5-dioxo-1,2,4-triazin-2(3H)-yl]-α-[3-(dimethylamino)propyl]-benzeneacetonitrile(interm. 41).

Example A.8

a) A mixture of(±)-4-amino-2,6-dichloro-α-[4-chloro-3-(trifluoromethyl)phenyl]-α-methylbenzeneacetonitrile(0.08 mol) in acetic acid (250 ml) and concentrated chloric acid (0.24mol) was stirred at ±10° C. A solution of sodium nitrite (0.08 mol) inwater (15 ml) was added dropwise over 30 minutes at ±10° C. The mixturewas stirred for one hour. Sodium acetate (0.24 mol) and carbamic acid,(1,3-dioxo-1,3-propanediyl)bis-, diethyl ester (0.088 mol) were added inone portion. The resulting reaction mixture was stirred for 2 hours atRT. The mixture was poured out into ice-water, and the resultingprecipitate was filtered off, washed with water, then dissolved inCH₂Cl₂. The organic solution was dried, filtered and the solventevaporated. A sample of the residue (2 g) was purified over silica gelon a glass filter (eluent: CH₂Cl₂/CH₃OH 99/1). The desired fractionswere collected and the solvent was evaporated. The residue was stirredin DIPE, filtered off, washed and dried, yielding 0.95 g of diethyl(A)-N,N′-[2-[[3,5-dichloro-4-[1-[4-chloro-3-(trifluoromethyl)phenyl]-1-cyanoethyl]phenyl]hydrazono]-1,3-dioxo-1,3-propanediyl]dicarbamate(interm. 42; [α]₂₀ ^(D)=+37.83° @ 20.3 mg/2 ml in methanol).

b) A solution of intermediate 42 (0.08 mol) and potassium acetate (0.08mol) in acetic acid (350 ml) was stirred and refluxed for 4 hours. Thesolvent was evaporated, yielding ethyl(A)-[[2-[3,5-dichloro-4-[1-[4-chloro-3-(trifluoromethyl)phenyl]-1-cyanoethyl]phenyl]-2,3,4,5-tetrahydro-3,5-dioxo-1,2,4-triazin-6-yl]carbonyl]carbamate(interm. 43).

c) A solution of intermediate 43 (0.08 mol) in concentrated chloric acid(100 ml) and acetic acid (350 ml) was stirred and refluxed overnight.The reaction mixture was poured out into ice-water, and the resultingprecipitate was filtered off, washed with water, then dissolved inCH₂Cl₂/CH₃OH 98/2. The organic solution was dried, filtered and thesolvent was evaporated, yielding(A)-2-[3,5-dichloro-4-[1-[4-chloro-3-(trifluoromethyl)phenyl]-1-cyanoethyl]phenyl]-2,3,4,5-tetrahydro-3,5-dioxo-1,2,4-triazine-6-carboxylicacid (interm. 44; [α]₂₀ ^(D)=+33.76° @ 20.38 mg/2 ml in methanol).

(B)-2-[3,5-dichloro-4-[1-[4-chloro-3-(trifluoromethyl)phenyl]-1-cyanoethyl]phenyl]-2,3,4,5-tetrahydro-3,5-dioxo-1,2,4-triazine-6-carboxylicacid was prepared in an analogous way (interm. 45).

B. Preparation of the Final Compounds

Example B.1

A mixture of intermediate 6 (0.044 mol) in mercaptoacetic acid (23 ml)was stirred at 175° C. for 2 hours. The mixture was cooled, poured outon ice, basified with K₂CO₃ and extracted with EtOAc. The organic layerwas separated, dried, filtered and the solvent was evaporated. Theresidue was purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH 99.5/0.5). The pure fractions were collected and thesolvent was evaporated. The residue was crystallized from diethyl ether.The precipitate was filtered off and dried, yielding 3.7 g (17.2%) of(±)-2,6-dichloro-α-[4-chloro-3-(trifluoromethyl)phenyl]-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-α-methylbenzeneacetonitrile(comp. 1.7)

Example B.2

Boron tribromide (0.01932 mol) was added dropwise at −70° C. to asolution of inter mediate 23 (0.00322 mol) in CH₂Cl₂ (20 ml). Themixture was stirred at −70° C. for 5 hours, then poured out into icewater, basified with K₂CO₃ and extracted with CH₂Cl₂. The organic layerwas separated, washed with H₂O, dried, filtered and the solvent wasevaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/CH₃OH 97.5/2.5). The pure fractions werecollected and the solvent was evaporated. The residue was dried,yielding 0.30 g of(±)-4-chloro-α-[2-chloro-3-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)phenyl]-α-methyl-3-(trifluoromethyl)benzeneacetonitrile(comp. 1.36).

Example B.3

2-methyl-2-propanol, potassium salt (0.0428 mol) was added in oneportion at 10° C. under N₂ flow to a mixture of1-[(isocyanomethyl)sulfonyl]-4-methylbenzene (0.0155 mol) in dimethylsulfoxide (19 ml). The mixture was stirred for 10 minutes. Intermediate29 (0.0119 mol) and methanol (0.9 ml) were added. The mixture wasstirred at RT for 4 hours, then poured out into water, neutralized withHCl (3N) and extracted with EtOAc. The organic layer was separated,washed with water, dried, filtered and the solvent was evaporated. Theresidue was purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH 99/1). The pure fractions were collected and the solventwas evaporated, yielding 2.39 g (46%) of(±)-4-chloro-α-[2-chloro-3-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)phenyl]-3-(trifluoromethyl)benzeneacetonitrile(comp. 1.38).

Example B.4

A mixture of intermediate 32 (18.4 g) and copper(I)cyanide (6.7 g) wasstirred for 30 minutes at 180° C. After cooling, the reaction mixturewas taken up in a mixture of CHCl₃/CH₃OH (90:10). The whole was filteredand the filtrate was evaporated. The residue was crystallized from amixture of CHCl₃/CH₃OH (98:2). The product was filtered off, washed with2,2′-oxybispropane and dried, yielding 6.7 g (37.3%) ofα-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetonitrile;(comp. 1.41; mp. 206.3° C.).

Example B.5

A mixture of2-chloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-α-methylbenzeneacetonitrile(0.01 mol) and triethylamine (0.01 mol) in pyridine (115 ml) was heatedat 60° C. H₂S was bubbled through the mixture for 5 hours. The mixturewas then stirred at 60° C. for 16 hours. H₂S was bubbled through themixture again for 8 hours and the mixture was then stirred at 60° C. for48 hours. H₂S was bubbled through the mixture for 3 days. The solventwas evaporated and the residue was taken up in CH₂Cl₂, washed with anHCl (3N) and with water, dried, filtered and the solvent was evaporated.The residue was purified by column chromatography over silica gel(eluent: CH₂Cl₂/CH₃OH 97/3). The pure fractions were collected and thesolvent was evaporated, yielding 1.5 g (36%) of(±)-2-chloro-a-(4-chlorophenyl)-α-methyl-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneethanethioamide(comp. 1.21)

Example B.6

a) Compound 2.8 (0.00474 mol) was added portionwise to H₂SO₄ (5 ml),acetic acid (5 ml) and H₂O (5 ml). The mixture was stirred at 140° C.for 14 hours and then poured out into H₂O. The precipitate was filteredoff, washed with H₂O, taken up in EtOAc, washed with H₂O, dried,filtered and the solvent was evaporated. The residue was crystallizedfrom EtOAc and diethyl ether. The precipitate was filtered off anddried, yielding 0.7 g (33%) of(±)-2,6-dichloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-α-methylbenzeneacetonitrile(comp. 1.11).

b) A mixture of2-chloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-α-methylbenzeneacetonitrile(0.026 mol) in H₂SO₄ (75 ml), acetic acid (75 ml) and H₂O (75 ml) wasstirred at 140° C. for 24 hours. H₂SO₄ (25 ml) and acetic acid (25 ml)were added again. The mixture was stirred and refluxed for 18 hours andthen poured out on ice. The precipitate was filtered off, taken up inEtOAc, washed with H₂O, dried, filtered and the solvent was evaporated.The residue was taken up in CH₂Cl₂, washed with H₂O, dried, filtered andthe solvent was evaporated. Part of this residue (1 g) was taken up inH₂O and NaOH 3N, treated with activated charcoal, filtered over celite,extracted with CH₂Cl₂ and separated into its layers. The aqueous layerwas acidified with HCl 3N and extracted with CH₂Cl₂. The combinedorganic layer was washed with H₂O, dried, filtered and the solvent wasevaporated, yielding 0.56 g(±)-2-chloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-α-methylbenzeneaceticacid (comp. 1.12)

Example B.7

a) A mixture of2-chloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneaceticacid (0.0178 mol) in thionyl chloride (30 ml) was stirred and refluxedfor 2 hours. The mixture was cooled and the solvent was evaporated,yielding 6.5 g of(±)-2-chloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetylchloride (comp. 1.5).

b) A mixture of compound 1.56 (0.0038 mol) in thionylchloride (11 ml)was stirred and refluxed for 2 hours. The solvent was evaporated,yielding(±)-2,6-dichloro-α-[4-chloro-3-(trifluoromethyl)phenyl]-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl]-benzeneacetylchloride (comp. 1.57).

Example B.8

A mixture of compound 1.5 (0.0158 mol), O,N-dimethylhydroxylamine(0.0237 mol) and triethylamine (0.0521 mol) in CH₂Cl₂ (150 ml) wasstirred at RT for 12 hours. The mixture was washed with K₂CO₃ (10%) andwith water, dried, filtered and the solvent was evaporated. The residuewas taken up in CH₂Cl₂, washed with HCl (3N) and with water, dried,filtered and the solvent was evaporated. The residue was purified bycolumn chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 98/2). Thepure fractions were collected and the solvent was evaporated. Theresidue was recrystallized from CH₃CN and diethyl ether. The precipitatewas filtered off and dried, yielding 2.15 g (34%) of(±)-2-chloro-α-(4-chlorophenyl)-N-methoxy-N-methyl-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetamide(comp. 1.6).

Example B.9

A solution of(±)-2-chloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-α-methylbenzeneacetylchloride (0.007 mol) in CH₂Cl₂ (20 ml) was added at RT to methanamine40% in water (0.105 mol). The mixture was stirred at RT for 4 hours,then poured out into water, acidified with HCl (3N) and extracted withCH₂Cl₂. The organic layer was separated, dried, filtered and the solventwas evaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/CH₃OH 97/3). The pure fractions werecollected and the solvent was evaporated, yielding 1.25 g (43%) of(±)-2-chloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-α,N-dimethylbenzeneacetamide(comp. 1.14).

Example B.10

n-Butyllithium, (1.6M solution in hexane; 0.0575 mol) was added at −70°C. under N₂ flow to a solution of benzothiazole (0.0575 mol) in THF (150ml), and the mixture was stirred at −70° C. for 30 minutes. Compound 1.6(0.0115 mol) in THF (100 ml) was added dropwise, the mixture was stirredat −70° C. for 3 hours, poured out into water and extracted with EtOAc.The organic layer was separated, dried, filtered, and the solvent wasevaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/CH₃OH 99/1). The pure fractions werecollected and the solvent was evaporated. The residue (1.7 g) wascrystallized from 2-propanone. The precipitate was filtered off anddried, yielding 1.35 g of(±)-2-[4-[2-(2-benzothiazolyl)-1-(4-chlorophenyl)-2-oxoethyl]-3-chlorophenyl]-1,2,4-triazin-3,5(2H,4H)-dione(comp. 1.20).

Example B.11

Acetic acid, ammonium salt (3 g) was added at RT to a solution of(±)-2-chloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-α-methylbenzeneacetylchloride (0.007 mol) in 2-propanone (30 ml). The mixture was stirred atRT for 5 hours. Acetic acid, ammonium salt was filtered off and thesolvent was evaporated. The residue was taken up in CH₂Cl₂, washed withwater, dried, filtered and the solvent was evaporated. The residue waspurified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH97/3). The pure fractions were collected and the solvent was evaporated,yielding 1.6 g (57%) of(±)-2-chloro-a-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-α-methylbenzeneacetamide(comp. 1.18).

Example B.12

A mixture of compound 1.68 (0.031 mol) in HBr in acetic acid (110 ml;33% solution) and HBr (65 ml; 48% aqueous solution) was stirred andrefluxed overnight and then poured out into ice water. The precipitatewas filtered off, washed with H₂O and taken up in CH₂Cl₂ and a smallamount of CH₃OH. The organic solution was dried, filtered and thesolvent was evaporated, yielding 13.6 g of(±)-2,6-dichloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl-α-methylbenzeneaceticacid; (comp. 1.69).

Example B.13

A mixture of intermediate (41) (0.00457 mol) in concentrated HCl (25 ml)and acetic acid (44 ml) was stirred and refluxed overnight. The mixturewas allowed to cool to RT, poured out on ice, basified with K₂CO₃ andextracted with CH₂Cl₂ and a small amount of CH₃OH. The organic layer wasseparated, dried, filtered and the solvent was evaporated. The residue(2.1 g) was purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/NH₄OH 90/10/1 and 70/30/1). The pure fractions werecollected and the solvent was evaporated. The residue was crystallizedfrom EtOAc and 2-propanone. The precipitate was filtered off and dried,yielding 0.95 g (45%) of(±)-2-chloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-α-[3-(dimethylamino)propyl]-benzeneacetonitrile;mp. 140° C. (Kofler) (comp. 1.58).

Example B.14

A mixture of compound 1.5 (0.05 mol) in THF (350 ml) was stirred at −75°C. A solution of chloro(phenylmethyl) magnesium (0.1 mol; 2 M/THF) inTHF (50 ml) was added dropwise over 1 hour at −75° C. The mixture wasstirred at −75° C. for 4 hours, then the temperature was raised to −20°C. and a saturated NH₄Cl solution (50 ml) was added dropwise over 15minutes. Water was added and the layers were separated. The organiclayer was evaporated. The residue was dissolved in CH₂Cl₂/CH₃OH 90/10.The organic layer was dried, filtered and the solvent was evaporated.The residue was stirred in CH₂Cl₂. The solid was filtered off, thefiltrate was evaporated and the residue was filtered over silica gelusing a mixture of CH₂Cl₂/CH₃OH 98/2 as eluent. The desired productfraction was collected and the solvent was evaporated, yielding 4.3 g(±)-2-[3-chloro-4-[1-(4-chlorophenyl)-2-oxo-3-phenylpropyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione(comp. 1.67).

Tables 2 to 5 list the compounds of formula (I) which were preparedaccording to one of the above examples (column “Ex. No.”)

TABLE 2

Comp. Ex. No. No. R¹ R² R^(3b) R^(3c) R^(4a) R^(4c) R^(4d) 1.1 B.1 CH₃CN H H Cl H H 1.2 B.5 H

H H H H H 1.3 B.1 CH₃ CN H H OCH₃ H H 1.4 B.1 CH₃ CN H CH₃ CF₃ H H 1.5B.7a H

H H H H H 1.6 B.8 H

H H H H H 1.7 B.1 CH₃ CN Cl H CF₃ H H 1.8 B.8 H

Cl H H H H 1.9 B.1 CH₃ CN Cl H Cl H H 1.10 B.9 H

H H H H H 1.11 B.6a CH₃

Cl H H H H 1.12 B.6b CH₃

H H H H H 1.13 B.7a CH₃

H H H H H 1.14 B.9 CH₃

H H H H H 1.15 B.10 H

H H H H H 1.16 B.5 CH₃

Cl H H H H 1.17 B.1 CH₃ CN H H CH₃ H H 1.18 B.11 CH₃

H H H H H 1.19 B.1 CH₃ CN H H H H Cl 1.20 B.10 H

H H H H H 1.21 B.5 CH₃

H H H H H 1.22 B.10 H

H H H H H 1.23 B.8 CH₃

H H H H H 1.24 B.9 CH₃

H H H H H 1.25 B.10 H

Cl H H H H 1.26 B.5 CH₃

Cl H CF₃ H H 1.27 B.5 H

Cl H CF₃ H H 1.28 B.5 CH₃

Cl H Cl H H 1.29 B.5 CH₃

H CH₃ CF₃ H H 1.30 B.10 H

H H H H H 1.31 B.5 CH₃

H H CF₃ H H 1.32 B.6b CH₃

H H CF₃ H H 1.33 B.7a CH₃

H H CF₃ H H 1.34 B.6b

H H H H H 1.53 B.1 CH₃ CN Cl H CF₃ H H 1.54 B.1 CH₃ CN Cl H CF₃ H H 1.55B.5 CH₃

H H CH₃ H H 1.56 B.6b H

Cl H CF₃ H H 1.57 B.7b H

Cl H CF₃ H H 1.58 B.13 (CH₂)₃—N(CH₃)₂ CN H H H H H 1.59 B.1 H CN Cl HCH₃ H H 1.60 B.5 H

Cl H CH₃ H H 1.61 B.14 H

Cl H H H H 1.62 B.14 H

Cl H H H H 1.63 B.1 CH₃ CN Cl H F H H 1.64 B.5 CH₃

Cl H F H H 1.65 B.1 H CN Cl H CH₃O H H 1.66 B.5 H

Cl H CH₃O H H 1.67 B.14 H

H H H H H 1.68 B.1 CH₃

Cl H H H H 1.69 B.12 CH₃

Cl H H H H 1.70 B.7a CH₃

Cl H H H H

TABLE 3

Comp. Ex. No. No. R¹ R^(3a) R^(3b) 1.35 B.2 CH₃ H Cl 1.36 B.2 CH₃ Cl H1.37 B.3 H H Cl 1.38 B.3 H Cl H

TABLE 4

Comp. Ex. No. No. R¹ R^(3a) R^(3b) R^(4a) R^(4b) R^(4c) R^(4d) 1.39 B.1H Cl Cl H H H H 1.40 B.1 H Cl Cl H OCH₃ H H 1.41 B.4 H H H H Cl H H 1.42B.1 CH₃ Cl H OCH₃ OCH₃ H H 1.43 B.1 CH₃ Cl H H OCH₃ H H 1.44 B.1 CH₃ ClH Cl OCH₃ H H 1.45 B.1 CH₃ OCH₃ H CF₃ Cl H H 1.46 B.1 CH₃ Cl H OCH₃ OCH₃OCH₃ H 1.47 B.1 CH₃ Cl H CH₃ OCH₃ H H 1.48 B.1 CH₃ H H H Cl H Cl 1.49B.1 CH₃ CH₃ H CF₃ Cl H H 1.50 B.1 CH₃ Cl H H phenyl H H 1.51 B.1 H Cl ClCF₃ Cl H H 1.52 B.2

Cl H H Cl H H 1.71 B.1 H CH₃ CH₃ Cl Cl H H 1.72 B.1 H Br Br H Cl H H

TABLE 5

Comp. Ex. No. No. R¹ R^(3a) R^(3b) R^(4a) 1.73 B.5 CH₃ CH₃O H CF₃ 1.74B.5 H CH₃ CH₃ Cl 1.75 B.5 H Br Br H

Table 6 lists both the experimental (column heading “Exp”) andtheoretical (column heading “Theor”) elemental analysis values forcarbon (C), hydrogen (H) and nitrogen (N) for the compounds as preparedin the experimental part hereinabove.

TABLE 6 Comp. C H N No. Theor Exp Theor Exp Theor Exp 1.1 51.27 51.282.63 2.21 13.29 13.06 1.2 50.13 49.72 2.97 2.62 13.76 12.95 1.3 54.6954.04 3.38 3.44 13.43 12.96 1.4 51.19 51.3 2.79 2.71 11.94 11.75 1.652.43 52.25 3.71 3.89 12.87 12.69 1.7 46.60 46.8 2.06 2.00 11.44 11.31.8 48.59 48.22 3.22 2.90 11.93 11.45 1.9 47.40 47.25 2.21 2.22 12.2811.95 1.11 49.17 49.47 2.98 3.11 12.74 11.92 1.12 53.22 51.73 3.23 3.1710.34 9.88 1.14 54.43 53.2 3.85 3.88 13.36 12.85 1.15 55.28 54.18 3.313.39 15.35 14.83 1.17 56.87 56.33 3.52 3.46 13.96 13.43 1.18 53.35 51.783.48 3.53 13.83 13.17 1.19 51.27 51.38 2.63 2.67 13.29 13.15 1.20 56.5956.45 2.77 2.66 11 10.77 1.21 51.32 49.63 3.35 3.35 13.3 12.62 1.22 52.354.18 2.63 2.9 12.2 11.54 1.23 53.47 52.5 4.04 3.93 12.47 12.14 1.2551.4 51.48 2.88 2.98 14.27 13.91 1.30 58.33 58.25 3.01 3.04 10.46 10.271.35 50.13 50.21 2.44 2.35 12.31 12.12 1.36 50.13 50.19 2.44 2.51 12.3111.79 1.37 49 49.34 2.06 1.88 12.7 12.45 1.42 58.19 58.31 4.15 4.2313.57 13.44 1.43 59.61 57.79 3.95 3.87 14.64 14.19 1.44 54.69 54.78 3.383.46 13.43 13.06 1.45 53.29 53.3 3.13 3.08 12.43 12.14 1.46 56.96 56.134.32 4.13 12.65 12.4 1.47 60.53 60.78 4.32 4.41 14.12 13.63 1.48 55.8355.83 3.12 3.08 14.47 14.30 1.49 55.25 55.36 3.25 3.21 12.89 12.90 1.5067.21 65.87 4.00 4.13 13.06 12.68 1.52 59.35 59.39 3.14 3.04 12.82 12.631.53 46.60 46.62 2.06 1.95 11.44 11.37 1.54 46.60 46.51 2.06 1.96 11.4411.44 1.58 57.65 56.55 4.62 4.65 15.28 14.12 1.61 57.56 57.62 3.22 3.228.39 8.45 1.71 56.87 56.69 3.52 3.58 13.96 13.41

C. Pharmacological Example

Example C.1 In Vitro Inhibition of IL-5 Production In Human Blood

Human Whole Blood Stimulation

Peripheral blood from healthy male donors was drawn into heparinizedsyringes (12.5 U heparin/ml). Blood samples were three-fold diluted inRMPI 1640 medium (Life Technologies, Belgium) supplemented with 2 mML-glutamine, 100 U/ml penicillin and 100 μg/ml streptomycin, and 300 μlfractions were distributed in 24-well multidisc plates. Blood sampleswere preincubated (60 minutes at 37° C.) in a humidified 6%CO₂-atmosphere with 100 μl of drug solvent (final concentration 0.02%dimethylsulfoxide in RPMI 1640) or with 100 μl of an appropriate dose oftest compound before being stimulated by the addition of 100 μl ofphytohemagglutinin HA17 (Murex, UK) at a final concentration of 2 μg/ml.After 48 hours, cell-free supernatant fluids were collected bycentrifugation and stored at −70° C. until tested for the presence ofIL-5.

IL-5 Measurements

IL-5 measurements were conducted as described in Van Wauwe et al. (1996,Inflamm Res, 45, 357-363) on page 358 using ELISA.

Table 8 lists the percentage inhibition of IL-5 production (column “%inhibition”) at a test dose of 1×10⁻⁶ M, or in case the percentageinhibition is marked with an “*” 1×10⁻⁵ M, for the compounds of thepresent invention including compounds of formula (I) which have beendisclosed in U.S. Pat. No. 4,631,278 (Ref. A) or U.S. Pat. No. 4,767,760(Ref. B) as summarized in table 7.

TABLE 7

Co. No. Ref R¹ R² R^(3a) R^(3b) R^(3c) R^(4a) R^(4b) 2.1 A CH₃ CN H H HH H 2.2 A CH₃ CN Cl H H H F 2.3 A CH₃ CN CF₃ H H H Cl 2.4 A4-chlorophenyl CN Cl H H H Cl 2.5 A (CH₂)₂—CH₃ CN Cl H H H Cl 2.6 A(CH₂)₃—CH₃ CN Cl H H H Cl 2.7 A CH₃ CN Cl H H CF₃ Cl 2.8 A CH₃ CN Cl ClH H Cl 2.9 A H CN Cl H H H Cl 2.10 A CH₃ CN Cl CH₃ H H Cl 2.11 A CH₃ CNCl H CH₃ H Cl 2.12 A H CN Cl Cl H H Cl 2.13 A H CN Cl H H H F 2.14 A HCN Cl H H H CH₃ 2.15 A CH₃ CN F H H H F 2.16 A H CN Cl Cl H H F 2.17 A HCN Cl CH₃ H H F 2.18 A H CN CH₃ CH₃ H H F 2.19 A H CN CH₃ CH₃ H H Cl2.20 B H C(═O)NHCH₃ Cl Cl H H Cl 2.21 B H

Cl Cl H H Cl 2.22 B H C(═O)CH₃ Cl Cl H H Cl 2.23 B H C(═S)NH₂ Cl Cl H HCl

TABLE 8 Co. No. % inhibition 1.1 63 1.2 11 1.3 40 1.4 87 1.6 49 1.7 921.8 42 1.9 84 1.11 12 1.14  9 1.15 70 1.17 63 1.19 49 1.20 80 1.21 331.23 62 1.24 12 1.25  6 1.35 33 1.36 44 1.37 12 1.39 31 1.41 13 1.42 221.43  5 1.44 46 1.45 41 1.46 33 1.47 38 1.48  2 1.49 69 1.50 24 1.53 951.54 95 1.58 28 1.61 72 1.71 23 2.1 14 2.2 22 2.3 37 2.4 16 2.5 67 2.681 2.7 85 2.8 87 2.9 21 2.10 81 2.11 53 2.12 37 2.13  48* 2.14 37 2.1514 2.16 10 2.17 23 2.18  9 2.19 20 2.20 31 2.21 25 2.22 83 2.23 47

D. Composition Examples

The following formulations exemplify typical pharmaceutical compositionssuitable for systemic or topical administration to animal and humansubjects in accordance with the present invention.

“Active ingredient” (A.I.) as used throughout these examples relates toa compound of formula (I) or a pharmaceutically acceptable addition saltthereof.

Example D.1 Film-Coated Tablets

Preparation of Tablet Core

A mixture of A.I. (100 g), lactose (570 g) and starch (200 g) was mixedwell and thereafter humidified with a solution of sodium dodecyl sulfate(5 g) and polyvinyl-pyrrolidone (10 g) in about 200 ml of water. The wetpowder mixture was sieved, dried and sieved again. Then there was addedmicrocrystalline cellulose (100 g) and hydrogenated vegetable oil (15g). The whole was mixed well and compressed into tablets, giving 10.000tablets, each comprising 10 mg of the active ingredient.

Coating

To a solution of methyl cellulose (10 g) in denaturated ethanol (75 ml)there was added a solution of ethyl cellulose (5 g) in dichloromethane(150 ml). Then there were added dichloromethane (75 ml) and1,2,3-propanetriol (2.5 ml). Polyethylene glycol (10 g) was molten anddissolved in dichloromethane (75 ml). The latter solution was added tothe former and then there were added magnesium octadecanoate (2.5 g),polyvinyl-pyrrolidone (5 g) and concentrated color suspension (30 ml)and the whole was homogenated. The tablet cores were coated with thethus obtained mixture in a coating apparatus.

Example D.2 2% Topical Cream

To a solution of hydroxypropyl β-cyclodextrine (200 mg) in purifiedwater is added A.I. (20 mg) while stirring. Hydrochloric acid is addeduntil complete dissolution and next sodium hydroxide is added until pH6.0. While stirring, glycerol (50 mg) and polysorbate 60 (35 mg) areadded and the mixture is heated to 70° C. The resulting mixture is addedto a mixture of mineral oil (100 mg), stearyl alcohol (20 mg), cetylalcohol (20 mg), glycerol monostearate (20 mg) and sorbate 60 (15 mg)having a temperature of 70° C. while mixing slowly. After cooling downto below 25° C., the rest of the purified water q.s. ad 1 g is added andthe mixture is mixed to homogenous.

What is claimed is:
 1. A method for treating an eosinophil-dependentinflammatory disease in a warm-blooded animal in need thereof comprisingadministering to the warm-blooded animal an effective amount of acompound of formula

a N-oxide, a pharmaceutically acceptable addition salt or astereochemically isomeric form thereof, wherein: p represents 0, 1, or2; q represents 0, 1, 2, or 3; R¹ hydrogen, C₁₋₆alkyl, aryl, mono-ordi(C₁₋₆alkyl)aminoC₁₋₆alkyl, or Het C₁₋₆alkyl; R² represents cyano or aradical of formula —C(═X)—Y—R⁵; wherein X represents O or S; Yrepresents O, S, NR⁶ or a direct bond; R⁵ represents hydrogen; C₁₋₆alkylor aryl; and where Y is a direct bond, R⁵ may also be halo, Het orC₁₋₆alkyl substituted with aryl; R⁶ represents hydrogen or C₁₋₆alkyloxy;each R³ independently represents halo, haloC₁₋₆alkyl, C₁₋₆alkyl,C₁₋₆alkyloxy, C₁₋₆alkylthio, or aryl; each R⁴ independently representshalo, haloC₁₋₆alkyl, C₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio, or aryl;aryl represents phenyl or phenyl substituted with one, two or threesubstituents selected from the group comprising halo, hydroxy, mercapto,and C₁₋₆alkyl; and Het represents optionally substituted imidazolyl,thiazolyl, piperazinyl, or benzothiazolyl.
 2. The method according toclaim 1 wherein the eosinophil-dependent inflammatory disease isbronchial asthma.
 3. The method according to claim 1 wherein theeosinophil-dependent inflammatory disease is atopic dermatitis.
 4. Themethod according to claim 1 wherein the eosinophil-dependentinflammatory disease is allergic rhinitis.
 5. The method according toclaim 1 wherein the eosinophil-dependent inflammatory disease isallergic conjunctivitis.
 6. The method according to claim 1 wherein the6-azauracil moiety is in the para position relative to the centralchiral carbon atom; p is 1 or 2 and one R³ substituent is chloropositioned ortho relative to the central chiral carbon atom; q is 1 or 2and one R⁴ substituent is chloro in the 4 position.
 7. A compound offormula

a N-oxide, a pharmaceutically acceptable addition salt or astereochemically isomeric form thereof, wherein p, q, R¹, R³ and R⁴ areas defined in claim 1, and; R² represents a radical of formula—C(═X)—Y—R⁵; wherein Y is a direct bond and R⁵ is Het as defined inclaim
 1. 8. A compound as claimed in claim 7 wherein the 6-azauracilmoiety is in the para position relative to the central chiral carbonatom; p is 1 or 2 and one R³ substituent is chloro positioned orthorelative to the central chiral carbon atom; q is 1 or 2 and one R⁴substituent is chloro in the 4 position.
 9. A compound as claimed inclaim 7 wherein R¹ is mono- or di(C₁₋₆alkyl)amino C₁₋₆alkyloxy,mercapto, C₁₋₆alkylthio or C₁₋₆alkyl substituted with mono- ordi(C₁₋₆alkyl)amino, C₁₋₆alkyloxy or Het.
 10. A process for preparing acompound of formula (I′) as claimed in claim 7, comprising, a) cyclizingan intermediate of formula (II) and eliminating an electron attractinggroup E from the thus obtained dione of formula (III):

b) eliminating a protective group P in the intermediates of formula(IV):

c) converting a hydroxyl function of an intermediate of formula (V) intoa suitable leaving group W, and subsequently converting said leavinggroup W in the thus formed intermediate of formula (VI) into a nitrilefunction; thus forming a compound of formula (I′-a):

d) reacting a carbonyl group in an intermediate of formula (VII) with1-[(isocyanomethyl)sulfonyl]-4-methylbenzene or a functional derivativethereof:

e) converting compounds of formula (I′) into each other followingart-known transformations, and optionally converting the compounds offormula (I′), into a therapeutically active non-toxic acid addition saltby treatment with an acid, or into a therapeutically active non-toxicbase addition salt by treatment with a base, or conversely, convertingthe acid addition salt form into the free base by treatment with alkali,or converting the base addition salt into the free acid by treatmentwith acid; and optionally preparing stereochemically isomeric forms orN-oxide forms thereof.
 11. A composition comprising a pharmaceuticallyacceptable carrier and, as active ingredient, a therapeuticallyeffective amount of a compound as claimed in claim
 7. 12. The method ofclaim 1, wherein said optionally substituted imidazolyl, thiazolyl,piperazinyl, or benzothiazolyl, comprises an imidazolyl, thiazolyl,piperazinyl, or benzothiazolyl substituted with one, two or threesubstituents selected from aryl and C₁₋₄alkyl.
 13. A compound of Formula(1):

wherein said compound is selected from the group consisting of: acompound wherein R¹ is H, wherein R² is

 wherein R^(3b) is H, wherein R^(3c) is H, wherein R^(4a) is H, whereinR^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ is H,wherein R² is

 wherein R^(3b) is H, wherein R^(3c) is H, wherein R^(4a) is H, whereinR^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ is H,wherein R² is

 wherein R^(3b) is H, wherein R^(3c) is H, wherein R^(4a) is H, whereinR^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ is H,wherein R² is

 wherein R^(3b) is Cl, wherein R^(3c) is H, wherein R^(4a) is H, whereinR^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ is H,wherein R² is

 wherein R^(3b) is H, wherein R^(3c) is H, wherein R^(4a) is H, whereinR^(4c) is H, and wherein R^(4d) is H; and  enantiomers, diastereomers,tautomers, solvates, and pharmaceutically acceptable salts thereof. 14.A method for treating an eosinophil-dependent inflammatory disease in awarm-blooded animal in need thereof comprising administering to thewarm-blooded animal an effective amount of a compound of Formula (1):

wherein said compound is selected from the group consisting of: acompound wherein R¹ is CH₃, wherein R² is CN, wherein R^(3b) H, where inR^(3c) is H, wherein R^(4a) is Cl, wherein R^(4c) is H, and whereinR^(4d) is H; a compound wherein R¹ is H, wherein R² is

 wherein R^(3b) is H, wherein R^(3c) is H, wherein R^(4a) is H, whereinR^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ is CH₃,wherein R² is CN, wherein R^(3b) is H, wherein R^(3c) is H, whereinR^(4a) is OCH₃, wherein R^(4c) is H, and wherein R^(4d) is H; a compoundwherein R¹ is CH₃, wherein R² CN, wherein R^(3b) is H, where in R^(3c)is CH₃, wherein R^(4a) is CF₃, wherein R^(4c) is H, and wherein R^(4d)is H; a compound wherein R¹ is H, wherein R² is

 wherein R^(3b) is H, wherein R^(3c) is H, wherein R^(4a) is H, whereinR^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ is H,wherein R² is

 wherein R^(3b) is H, wherein R^(3c) is H, wherein R^(4a) is H, whereinR^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ is CH₃,wherein R² is CN, wherein R^(3b) is Cl, where in R^(3c) is H, whereinR^(4a) is CF₃, wherein R^(4c) is H, and wherein R^(4d) is H; a compoundwherein R¹ is H, wherein R² is

 wherein R^(3b) is Cl, wherein R^(3c) is H, wherein R^(4a) is H, whereinR^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ is CH₃,wherein R² is CN, wherein R^(3b) is Cl, wherein R^(3c) is H, whereinR^(4a) is Cl, wherein R^(4c) is H, and wherein R^(4d) is H; a compoundwherein R¹ is H, wherein R² is

 wherein R^(3b) is H, wherein R^(3c) is H, wherein R^(4a) is H, whereinR^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ is CH₃,wherein R² is

 wherein R^(3b) is Cl, wherein R^(3c) is H, wherein R^(4a) is H, whereinR^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ is CH₃,wherein R² is

 wherein R^(3b) is H, wherein R^(3c) is H, wherein R^(4a) is H, whereinR^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ is CH₃,wherein R² is

 wherein R^(3b) is H, wherein R^(3c) is H, wherein R^(4a) is H, whereinR^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ is CH₃,wherein R² is

 wherein R^(3b) is H, wherein R^(3c) is H, wherein R^(4a) is H, whereinR^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ is H,wherein R² is

 wherein R^(3b) is H, wherein R^(3c) is H, wherein R^(4a) is H, whereinR^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ is CH₃,wherein R² is

 wherein R^(3b) is Cl, wherein R^(3c) is H, wherein R^(4a) is H, whereinR^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ is CH₃,wherein R² is CN, wherein R^(3b) is H, wherein R^(3c) is H, whereinR^(4a) is CH₃, wherein R^(4c) is H, and wherein R^(4d) is H; a compoundwherein R¹ is CH₃, wherein R² is

 wherein R^(3b) is H, wherein R^(3c) is H, wherein R^(4a) is H, whereinR^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ is CH₃,wherein R² is CN, wherein R^(3b) is H, where in R^(3c) is H, whereinR^(4a) is H, wherein R^(4c) is H, and wherein R^(4d) is Cl; a compoundwherein R¹ is H, wherein R² is

 wherein R^(3b) is H, wherein R^(3c) is H, wherein R^(4a) is H, whereinR^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ is CH₃,wherein R² is

 wherein R^(3b) is H, wherein R^(3c) is H, wherein R^(4a) is H, whereinR^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ is H,wherein R² is

 wherein R^(3b) is H, wherein R^(3c) is H, wherein R^(4a) is H, whereinR^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ is CH₃,wherein R² is

 wherein R^(3b) is H, wherein R^(3c) is H, wherein R^(4a) is H, whereinR^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ is CH₃,wherein R² is

 wherein R^(3b) is H, wherein R^(3c) is H, wherein R^(4a) is H, whereinR^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ is H,wherein R² is

 wherein R^(3b) is Cl, wherein R^(3c) is H, wherein R^(4a) is H, whereinR^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ is CH₃,wherein R² is

 wherein R^(3b) is Cl, wherein R^(3c) is H, wherein R^(4a) is CF₃,wherein R^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ isH, wherein R² is

 wherein R^(3b) is Cl, wherein R^(3c) is H, wherein R^(4a) is CF₃,wherein R^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ isCH₃, wherein R² is

 wherein R^(3b) is Cl, wherein R^(3c) is H, wherein R^(4a) is Cl,wherein R^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ isCH₃, wherein R² is

 wherein R^(3b) is H, wherein R^(3c) is CH₃, wherein R^(4a) is CF₃,wherein R^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ isH, wherein R² is

 wherein R^(3b) is H, wherein R^(3c) is H, wherein R^(4a) is H, whereinR^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ is CH₃,wherein R² is

 wherein R^(3b) is H, wherein R^(3c) is H, wherein R^(4a) is CF₃,wherein R^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ isCH₃, wherein R² is

 wherein R^(3b) is H, wherein R^(3c) is H, wherein R^(4a) is CF₃,wherein R^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ isCH₃, wherein R² is

 wherein R^(3b) is H, wherein R^(3c) is H, wherein R^(4a) is CF₃,wherein R^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ is

 wherein R² is

 wherein R^(3b) is H, wherein R^(3c) is H, wherein R^(4a) is H, whereinR^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ is CH₃,wherein R² is CN, wherein R^(3b) is Cl, wherein R^(3c) is H, whereinR^(4a) is CF₃, wherein R^(4c) is H, and wherein R^(4d) is H; a compoundwherein R¹ is CH₃, wherein R² is CN, wherein R^(3b) is Cl, whereinR^(3c) is H, wherein R^(4a) is CF₃ wherein R^(4c) is H and whereinR^(4d) is H; a compound wherein R¹ is CH₃, wherein R² is

 wherein R^(3b) is H, wherein R^(3c) is H, wherein R^(4a) is CH₃,wherein R^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ isH, wherein R² is

 wherein R^(3b) is Cl, wherein R^(3c) is H, wherein R^(4a) is CF₃,wherein R^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ isH, wherein R² is

 wherein R^(3b) is Cl, wherein R^(3c) is H, wherein R^(4a) is CF₃,wherein R^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ is(CH₂)₃—N(CH₃)₂, wherein R is CN, wherein R^(3b) is H, wherein R^(3c) isH, wherein R^(4a) is H, wherein R^(4c) is H, and wherein R^(4d) is H; acompound wherein R¹ is H, wherein R² CN, wherein R^(3b) is Cl whereinR^(3c) is H, wherein R^(4a) is CH₃, wherein R^(4c) is H, and whereinR^(4d) is H; a compound wherein R¹ is H, wherein R² is

 wherein R^(3b) is Cl, wherein R^(3c) is H, wherein R^(4a) CH₃, whereinR^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ is H,wherein R² is

 wherein R^(3b) is Cl, wherein R^(3c) is H, wherein R^(4a) is H, whereinR^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ is H,wherein R² is

 wherein R^(3b) is Cl, wherein R^(3c) is H, wherein R^(4a) is H, whereinR^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ is CH₃,wherein R² is CN, wherein R^(3b) is Cl, wherein R^(3c) is H, whereinR^(4a) is F, wherein R^(4c) is H, and wherein R^(4d) is H; a compoundwherein R¹ is CH₃, wherein R² is

 wherein R^(3b) is Cl, wherein R^(3c) is H, wherein R^(4a) is F, whereinR^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ is H,wherein R² is CN, wherein R^(3b) is Cl, wherein R^(3c) is H, whereinR^(4a) is CH₃O, wherein R^(4c) is H, and wherein R^(4d) is H; a compoundwherein R¹ is H, wherein R² is

 wherein R^(3b) is Cl, wherein R^(3c) is H, wherein R^(4a) is CH₃O,wherein R^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ isH, wherein R² is

 wherein R^(3b) is H, wherein R^(3c) is H, wherein R^(4a) is H, whereinR^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ is CH₃,wherein R² is

 wherein R^(3b) is Cl, wherein R^(3c) is H, wherein R^(4a) is H, whereinR^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ is CH₃,wherein R² is

 wherein R^(3b) is Cl, wherein R^(3c) is H, wherein R^(4a) is H, whereinR^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ is CH₃,wherein R² is

 wherein R^(3b) is Cl, wherein R^(3c) is H, wherein R^(4a) is H, whereinR^(4c) is H, and wherein R^(4d) is H; and enantiomers, diastereomers,tautomers, solvates, and pharmaceutically acceptable salts thereof. 15.A method for treating an eosinophil-dependent inflammatory disease in awarm-blooded animal in need thereof comprising administering to thewarm-blooded animal an effective amount of a compound of the followingFormula:

wherein said compound is selected from the group consisting of: acompound wherein R¹ is CH₃, wherein R^(3a) is H, and wherein R^(3b) isCl; a compound wherein R¹ is CH₃, wherein R^(3a) is Cl, and whereinR^(3b) is H; a compound wherein R¹ is H, wherein R^(3a) is H, andwherein R^(3b) is Cl; a compound wherein R¹ is H, wherein R^(3a) is Cl,and wherein R^(3b) is H; and enantiomers, diastereomers, tautomers,solvates, and pharmaceutically acceptable salts thereof.
 16. A methodfor treating an cosinophil-dependent inflammatory disease in awarm-blooded animal in need thereof comprising administering to thewarm-blooded animal an effective amount of a compound of the followingFormula:

wherein said compound is selected from the group consisting of: acompound wherein R¹ is H, wherein R^(3a) is Cl, wherein R^(3b) is Cl,wherein R^(4a) is H, wherein R^(4b) is H, wherein R^(4c) is H, andwherein R^(4d) is H; a compound wherein R¹ is H, wherein R^(3a) is Cl,wherein R^(3b) is Cl, wherein R^(4a) is H, wherein R^(4b) is OCH₃,wherein R^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ isH, wherein R^(3a) is H, wherein R^(3b) is H, wherein R^(4a) is H,wherein R^(4b) is Cl, wherein R^(4c) is H, and wherein R^(4d) is H; CH₃,wherein R^(3a) is Cl, wherein R^(3b) is H, wherein R^(4a) is OCH₃,wherein R^(4b) is OCH₃, wherein R^(4c) is H, and wherein R^(4d) is H; acompound wherein R¹ is CH₃, wherein R^(3a) is Cl, wherein R^(3b) is H,wherein R^(4a) is H, wherein R^(4b) is OCH₃, wherein R^(4c) is H, andwherein R^(4d) is H; a compound wherein R¹ is CH₃, wherein R^(3a) is Cl,wherein R^(3b) is H, wherein R^(4a) is Cl, wherein R^(4b) is OCH₃,wherein R^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ isCH₃, wherein R^(3a) is OCH₃, wherein R^(3b) is H, where in R^(4a) isCF₃, wherein R^(4b) is Cl, wherein R^(4c) is H, and wherein R^(4d) is H;a compound wherein R¹ is CH₃, wherein R^(3a) is Cl, wherein R^(3b) is H,wherein R^(4a) is OCH₃, wherein R^(4b) is OCH₃, wherein R^(4c) is OCH₃,and wherein R^(4d) is H; a compound wherein R¹ is CH₃, wherein R^(3a) isCl, wherein R^(3b) is H, wherein R^(4a) is CH₃, wherein R^(4b) is OCH₃,wherein R^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ isCH₃, wherein R^(3a) is H, wherein R^(3b) is H, wherein R^(4a) is H,wherein R^(4b) is Cl, wherein R^(4c) is H, and wherein R^(4d) is Cl; acompound wherein R¹ is CH₃, wherein R^(3a) is CH₃ wherein R^(3b) is H,wherein R^(4a) is CF₃, wherein R^(4b) is Cl, wherein R^(4c) is H, andwherein R^(4d) is H; a compound wherein R¹ is CH₃, wherein R^(3a) is Cl,wherein R^(3b) is H, wherein R^(4a) is H, wherein R^(4b) is phenyl,wherein R^(4c) is H, and wherein R^(4d) is H; a compound wherein R¹ isH, wherein R^(3a) is Cl, wherein R^(3b) is Cl, wherein R^(4a) is CF₃,wherein R^(4b) is Cl wherein R^(4c) is H, and wherein R^(4d) is H; acompound wherein R¹ is

 wherein R^(3a) is Cl, wherein R^(3b) is H, wherein R^(4a) is H, whereinR^(4b) is Cl, wherein R^(4c) is H, and wherein R^(4d) is H; H, whereinR^(3a) is CH₃, wherein R^(3b) is CH₃, wherein R^(4a) is Cl, whereinR^(4b) is Cl, wherein R^(4c) is H, and wherein R^(4d) is H; a compoundwherein R¹ is H, wherein R^(3a) is Br, wherein R^(3b) is Br, whereinR^(4a) is H, wherein R^(4b) is Cl, wherein R^(4c) is H, and whereinR^(4d) is H; and enantiomers, diastereomers, tautomers, solvates, andpharmaceutically acceptable salts thereof.
 17. A method for treating aneosinophil-dependent inflammatory disease in a warm-blooded animal inneed thereof comprising administering to the warm-blooded animal aneffective amount of a compound of the following Formula:

wherein said compound is selected from the group consisting of: acompound wherein R¹ is CH₃, wherein R^(3a) is CH₃O, wherein R^(3b) is H,and wherein R^(4a) is CF₃; a compound wherein R¹ is H, wherein R^(3a) isCH₃, wherein R^(3b) is CH₃, and wherein R^(4a) is Cl; a compound whereinR¹ is H, wherein R^(3a) is Br, wherein R^(3b) is Br, and wherein R^(4a)is H; and enantiomers, diastereomers, tautomers, solvates, andpharmaceutically acceptable salts thereof.
 18. A method for treating aneosinophil-dependent inflammatory disease in a warm-blooded animal inneed thereof comprising administering to the warm-blooded animal aneffective amount of a compound of the following Formula:

wherein said compound is selected from the group consisting of: acompound wherein R¹ is CH₃, wherein R² is CN, wherein R^(3a) is H,wherein R^(3b) is H, wherein R^(3c) is H, wherein R^(4a) is H andwherein R^(4b) is H; a compound wherein R¹ is CH₃, wherein R² is CN,wherein R^(3a) is Cl, wherein R^(3b) is H, wherein R^(3c) is H, whereinR^(4a) is H, and wherein R^(4b) is F; a compound wherein R¹ is CH₃,wherein R² is CN, wherein R^(3a) is CF₃, wherein R^(3b) is H, whereinR^(3c) is H, wherein R^(4a) is H, herein R^(4b) is Cl; a compoundwherein R¹ is 4-chlorophenyl, wherein R² is CN, wherein R^(3a) is Cl,wherein R^(3b) is H, wherein R^(3c) is H, wherein R^(4a) is H, andwherein R^(4b) is Cl; a compound wherein R¹ is (CH₂)₂-CH₃, wherein R² isCN, wherein R^(3a) is Cl, wherein R^(3b) is H, wherein R^(3c) is H,wherein R^(4a) is H, and wherein R^(4b) is Cl; a compound wherein R¹ is(CH₂)₃-CH₃, wherein R² is CN, wherein R^(3a) is Cl, wherein R^(3b) is H,wherein R^(3c) is H, wherein R^(4a) is H, and wherein R^(4b) is Cl; acompound wherein R¹ is CH₃, wherein R² is CN, wherein R^(3a) is Cl,wherein R^(3b) is H, wherein R^(3c) is H, wherein R^(4a) is CF₃ andwherein R^(4b) is Cl; a compound wherein R¹ is CH₃, wherein R² is CN,wherein R^(3a) is Cl, wherein R^(3b) is Cl, wherein R^(3c) is H, whereinR^(4a) is H, and wherein R^(4b) is Cl; a compound wherein R¹ is H,wherein R² is CN, wherein R^(3a) is Cl, wherein R^(3b) is H, whereinR^(3c) is H, wherein R^(4a) is H, and wherein R^(4b) is Cl; a compoundwherein R¹ is CH₃, wherein R² is CN, wherein R^(3a) is Cl, whereinR^(3b) is CH₃, wherein R^(3c) is H, wherein R^(4a) is H, wherein R^(4b)is Cl; a compound wherein R¹ is CH₃, wherein R² is CN, wherein R^(3a) isCl, wherein R^(3b) is H, wherein R^(3c) is CH₃, wherein R^(4a) is H, andwherein R^(4b) is Cl; a compound wherein R¹ is H, wherein R² is CN,wherein R^(3a) is Cl, wherein R^(3b) is Cl, wherein R^(3c) is H, whereinR^(4a) is H, and wherein R^(4b) is Cl; a compound wherein R¹ is H,wherein R² is CN, wherein R^(3a) is Cl, wherein R^(3b) is H, whereinR^(3c) is H, wherein R^(4a) is H, and wherein R^(4b) is F; a compoundwherein R¹ is H, wherein R² is CN, wherein R^(3a) is Cl, wherein R^(3b)is H, wherein R^(3c) is H, wherein R^(4a) is H, and wherein R^(4b) isCH₃; a compound wherein R¹ is CH₃, wherein R² is CN, wherein R^(3a) isF, wherein R^(3b) is H, wherein R^(3c) is H, wherein R^(4a) is H, andwherein R^(4b) is F; a compound wherein R¹ is H, wherein R² is CN,wherein R^(3a) is Cl, wherein R^(3b) is Cl, wherein R^(3c) is H, whereinR^(4a) is H, and wherein R^(4b) is F; a compound wherein R¹ is H,wherein R² is CN, wherein R^(3a) is Cl, wherein R^(3b) is CH₃, whereinR^(3c) is H, wherein R^(4a) is H, and wherein R^(4b) is F; a compoundwherein R¹ is H, wherein R² is CN, wherein R^(3a) is CH₃, wherein R^(3b)is CH₃, wherein R^(3c) is H, wherein R^(4a) is H, wherein R^(4b) is F; acompound wherein R¹ is H, wherein R² is CN, wherein R^(3a) is CH₃,wherein R^(3b) is CH₃, wherein R^(3c) is H, wherein R^(4a) is H, andwherein R^(4b) is Cl; a compound wherein R¹ is H, wherein R² isC(═O)NHCH₃, wherein R^(3a) is Cl, wherein R^(3b) is Cl, wherein R^(3c)is H, wherein R^(4a) is H, and wherein R^(4b) is Cl; a compound whereinR¹ is H, wherein R² is

 wherein R^(3a) is Cl, wherein R^(3b) is Cl, wherein R^(3c) is H,wherein R^(4a) is H, and wherein R^(4b) is Cl; a compound wherein R¹ isH, wherein R² is C(═O)CH₃, wherein R^(3a) is Cl, wherein R^(3b) is Cl,wherein R^(3c) is H, wherein R^(4a) is H, and wherein R^(4b) is Cl; acompound wherein R¹ is H, wherein R² is C(═S)NH₂, wherein R^(3a) is Cl,wherein R^(3b) is Cl, wherein R^(3c) is H, wherein R^(4a) is H, andwherein R^(4b) is Cl; and enantiomers, diastereomers, tautomers,solvates, and pharmaceutically acceptable salts thereof.